Patent Publication Number: US-2017356051-A1

Title: Method for estimating sensitivity to drug therapy for colorectal cancer

Description:
TECHNICAL FIELD 
     Related Application 
     The present description includes the contents as disclosed in the description of Japanese Patent Application No. 2014-212503 (filed on Oct. 17, 2014), which is a priority document of the present application. The present invention relates to a method for predicting responsiveness to anti-cancer therapy for colorectal cancer. More particularly, the present invention relates to a method for predicting sensitivity to anti-cancer therapy for colorectal cancer, using, as an indicator, DNA methylation profiles in a specimen containing a colorectal cancer tissue, colorectal cancer cells, or colorectal cancer cell-derived DNA of a colorectal cancer patient. 
     Background Art 
     With regard to the number of affected patients, colorectal cancer holds the second place in men and the first place in women, among all malignant tumors. With regard to the number of deaths, colorectal cancer comes in the third place (approx. 40,000 people in year 2004), and it is predicted that the number of deaths due to colorectal cancer will further increase in year 2015 (approx. 66,000 people). It is considered that the improvement of the treatment results of colorectal cancer will greatly contribute to a decrease in the number of deaths due to colorectal cancer, which accounts for 30% of a total number of deaths from cancer. 
     At present, metastatic colorectal cancer, which cannot be subjected to curative resection, can be treated by chemotherapies based on an irinotecan and based on oxaliplatin. The order in which these agents are applied in the combined use thereof has not been particularly studied. 
     On the other hand, as a result of the introduction of molecular targeted drugs, and in particular, the introduction of anti-EGFR antibody drugs (cetuximab and panitumumab) and an anti-VEGF antibody drug (bevacizumab), the treatment results (progression-free survival and overall survival) of metastatic colorectal cancer have been steadily improved. However, such molecular targeted drugs are expensive, and at the present moment, the cost-effectiveness of the molecular targeted drugs is inferior to that of conventional chemotherapeutic agents or molecular targeted drugs used for other cancers. From the viewpoint of avoiding the side effects of invalid patients that would cause unnecessary health care costs, it is necessary to selectively apply treatments to more effective subjects. 
     With regard to a biomarker for predicting the therapeutic sensitivity of metastatic colorectal cancer to anti-EGFR antibody drugs, it has been reported in 2008 that anti-EGFR antibody drugs do not increase therapeutic effects in the case of having a mutation on exon 2 of KRAS. Moreover, in clinical studies conducted in recent years, it has been reported that the effects of anti-EGFR antibody drugs are further increased in the case of wild-type RAS that does not have mutations on exons 3 and 4 as well as exon 2 of KRAS and exons 2, 3 and 4 of NRAS. Furthermore, a PIK3CA mutation is promising as a therapeutic effect predicting factor, and further, a BRAF mutation has been reported as a prognosis predicting factor, so far. 
     However, in the case of wild-type exon 2 of KRAS, which is a widely used biomarker at present, an increase in the response rate by the use of an anti-EGFR antibody drug is merely about 30%, and this is not considered to be sufficient. Even taking into consideration the aforementioned other genetic mutations, it is considered difficult to identify an authentic sensitivity group only by an analysis based on genetic mutation. 
     In contrast, Aburatani et al. have reported a method which comprises analyzing the methylation state of a marker gene in DNA extracted from a biological sample, and then determining the presence or absence of cancer cells in the biological sample or the prognosis of a colorectal cancer patient based on the obtained results (Patent Literature 1). Moreover, Yagi et al. have reported that when HME (a highly-methylated group) is extracted based on the methylation state of a first gene group, and IME (an intermediately-methylated group) and LME (a low-methylated group) are then extracted based on the methylation state of a second gene group, and thus, when a colorectal cancer patient group is classified into three subtypes, the survival period of IME (including a KRAS gene mutation) is found to be shortest (Non Patent Literature 1). 
     As a method for enabling a selective treatment of colorectal cancer, Ishioka et al. have reported a method which comprises comprehensively analyzing the expression levels of genes in colorectal cancer tissues, and attributing the results to any one of previously classified four groups, so as to predict the responsiveness of a colorectal cancer patient to an anti-EGFR antibody (Patent Literature 2). 
     A group from Sapporo Medical University has reported that the methylation level of LINE-1 is positively correlated with the expression level of microRNA-31 in a colorectal cancer patient, and that with regard to progression-free survival in cases of administration of an anti-EGFR antibody drug, the progression-free survival in a microRNA-31 high expression group is significantly shorter than that in a low expression group (Non Patent Literature 2). 
     Furthermore, Lee et al. have proposed a hypothesis that the DNA methylation of a CpG island would be associated with the biological properties of cancer, and that sensitivity to an anti-EGFR antibody would be influenced by the methylation state of DNA (Non Patent Literature 3). 
     CITATION LIST 
     Patent Literature 
     
         
         Patent Literature 1: Japanese Patent Laid-Open No. 2013-183725 
         Patent Literature 2: WO 2011/002029 
       
    
     Non Patent Literature 
     
         
         Non Patent Literature 1: Yagi K. et al., Clin Cancer Res. 2010 Jan. 1; 16(1): 21-33 
         Non Patent Literature 2: Katsuhiko NOSHO, Daiwa Securities Health Foundation, Year 2012, (39th) Search Study Subsidy Report 
         Non Patent Literature 3: Michael Sangmin Lee et al., ASCO Annual Meeting 2014, Abstract Number 3533 (http://meetinglibrary.asco.org/content/134359-144) 
       
    
     SUMMARY OF INVENTION 
     Technical Problem 
     In guidelines for administration of an anti-EGFR antibody used as a therapeutic agent for metastatic colorectal cancer, a method of administering the present antibody only to patients having a wild-type KRAS gene has been recommended. However, there are not a few cases where even wild-type KRAS gene patients show resistance to the anti-EGFR antibody. Hence, administration of the expensive anti-EGFR antibody to patients who are resistant to the present antibody causes high economical and/or physical burdens on the patients, and thus, it has been desired to develop guidelines for administration of the anti-EGFR antibody, which provide higher cost-effectiveness to the patients. 
     The present invention has been made under the aforementioned circumstances. It is an object of the present invention to predict with high precision the responsiveness of colorectal cancer to anti-cancer therapy, to reduce economical and/or physical burdens on patients, and to provide administration guidelines causing higher cost-effectiveness. 
     Solution to Problem 
     The present inventors have comprehensively analyzed the level of DNA methylation in the tissues from colorectal cancer patients. As a result, the inventors have found that the treatment results of anti-cancer therapy on a low-methylated group are significantly higher than those on a highly-methylated group, thereby completing the present invention. 
     Specifically, the present invention provides the following [1] to [14]. 
     [1] A method for predicting the responsiveness of a colorectal cancer patient to cancer drug therapy, the method comprising analyzing a level of DNA methylation in a specimen comprising a colorectal cancer tissue, colorectal cancer cells, or colorectal cancer cell-derived DNA of a subject, and then determining the responsiveness of the subject to cancer drug therapy based on the level of DNA methylation;
 
[2] the method according to the above [1], which comprises the following steps:
 
(1) a step of measuring a level of DNA methylation in a specimen comprising a colorectal cancer tissue, colorectal cancer cells, or colorectal cancer cell-derived DNA of a subject,
 
(2) a step of defining a gene having a β value of 0.5 or more as methylation positive, and then, classifying the subject into a highly-methylated group when the ratio of a methylation-positive gene is 60% or more, and classifying the subject into a low-methylated group when the ratio of a methylation-positive gene is less than 60%, and
 
(3) a step of determining that the subject is sensitive to cancer drug therapy when the subject is classified into the low-methylated group, and determining that the subject is resistant to cancer drug therapy when the subject is classified into the highly-methylated group;
 
[3] the method according to the above [1] or [2], wherein the analysis is carried out on at least 4 or more marker genes, as targets, selected from a group of genes having a significant difference in the β value between the highly-methylated group and the low-methylated group;
 
[4] the method according to the above [1] or [2], wherein the analysis is carried out on at least 4 or more marker genes, as targets, selected from a group of genes shown in Table 7 or a group of genes shown in Table 8, and for example, the method according to the above [1] or [2], wherein the analysis is carried out on the group of genes shown in Table 8 as targets;
 
[5] the method according to the above [1] or [2], wherein the analysis is carried out on 4 to 20 marker genes, as targets, selected from a group of genes shown in Table 7 or a group of genes shown in Table 8;
 
[6] the method according to the above [1] or [2], wherein the analysis is carried out on 4 to 10 marker genes, as targets, selected from a group of genes shown in Table 7 or a group of genes shown in Table 8;
 
[7] the method according to any one of the above [4] to [6], wherein the marker genes include at least one or more gene selected from the 24 genes shown in Table 8, or CACNA1G, LOX, SLC30A10, ELMO1, HAND1, IBN2 and THBD;
 
[8] the method according to any one of the above [1] to [7], wherein the cancer drug therapy is chemotherapy;
 
[9] the method according to any one of the above [1] to [7], wherein the cancer drug therapy is a therapy using a molecular targeted drug;
 
[10] the method according to the above [9], wherein the molecular targeted drug is an anti-EGFR antibody;
 
[11] the method according to any one of the above [1] to [10], wherein the suitability of the order of cancer drug therapies can be determined;
 
[12] a probe set for predicting the responsiveness of a colorectal cancer patient to cancer drug therapy, wherein
 
     the probe set comprises a probe which comprises a sequence complementary to a region comprising a CpG site of at least one of, 4 or more marker genes selected from a group of genes shown in Table 7 or a group of genes shown in Table 8, and for example, all the genes in the group of genes shown in Table 8, and which is capable of detecting the presence or absence of the methylation of the CpG site; 
     [13] the probe set according to the above [12], wherein the marker genes comprise one or more genes selected from the group of genes shown in Table 8, or CACNA1G, LOX, SLC30A10, ELMO1, HAND1, IBN2 and THBD;
 
[14] a kit for predicting the responsiveness of a colorectal cancer patient to cancer drug therapy, wherein the kit comprises:
 
(a) a probe which comprises a sequence complementary to a region comprising a CpG site of at least one of, 4 or more genes selected from a group of genes shown in Table 7 or a group of genes shown in Table 8, and for example, all the genes in the group of genes shown in Table 8, and which is capable of detecting the presence or absence of the methylation of the CpG site, and
 
(b) a primer pair which binds to a region comprising a CpG site of at least one of, 4 or more genes selected from a group of genes shown in Table 7 or a group of genes shown in Table 8, and for example, all the genes in the group of genes shown in Table 8, and which is capable of amplifying the region comprising the CpG site; and
 
[15] the kit according to the above [14], wherein the marker genes comprise one or more genes selected from the 24 genes shown in Table 8, or CACNA1G, LOX, SLC30A10, ELMO1, HAND1, IBN2 and THBD.
 
     To date, phenotype classification based on methylation profiles including CIMP as a typical example has been reported with regard to colorectal cancer or several other cancers. However, the correlation of drug sensitivity with methylation has not yet been reported, and thus, it is not easy to predict from previous reports the presence of the correlation of methylation profiles with drug sensitivity. That is to say, the present invention is a first report regarding possible prediction of drug sensitivity from methylation profiles. 
     Advantageous Effects of Invention 
     According to the present invention, it becomes possible to select chemotherapy for colorectal cancer, and particularly, unresectable metastatic colorectal cancer, based on a difference in methylation state. Specifically, when a primary treatment is started, with regard to the regimens of irinotecan-based and oxaliplatin-based chemotherapies, both of which are considered to be favorable at present, the order in which the regimens are applied can be selected based on the DNA methylation state of a specimen derived from a patient. 
     In addition, according to the present invention, a case group, which shows resistance to an anti-EGFR antibody drug even if it is wild-type KRAS, can be extracted. Moreover, even the recently reported wild-type RAS cases having no mutations on exons 3 and 4 as well as exon 2 of KRAS, and on exons 2, 3 and 4 of NRAS, which are included in a treatment-resistant group, can be extracted. That is to say, the method of the present invention can extract actually resistant cases from cases that have been classified into a treatment-sensitive group according to conventional reports, and thus, the present method is considered to be a method for predicting therapeutic effects with higher precision. 
     Genetic mutations are successively accumulated in the onset and/or progression of a cancer, and subpopulations having various genetic mutation profiles are present in tumor (heterogeneity). In the case of colorectal cancer, accumulation of genetic mutations is highly likely to occur in the onset and/or progression of a tumor, and colorectal cancer is a tumor rich in heterogeneity. Accordingly, when genetic mutations are to be examined in colorectal cancer, the results are strongly influenced by at what time point in the therapeutic process, from what site, from what range of tumor, DNA was extracted. 
     In contrast, it is considered that methylation profiles are determined in the initial stage of canceration, and thus, it can be said that the methylation profiles are relatively uniform in a tumor. That is, it is expected that, when compared with a diagnosis based on genetic mutation, the method of the present invention suppresses a variation in the results caused by the aforementioned specimen collection conditions, and also more precisely reflects methylation profiles in a tumor at the start of use of a molecular targeted drug, even if it is a specimen collected upon resection of a primary lesion. Specifically, the method of the present invention can precisely determine the therapeutic effects of cancer drug therapy, regardless of the state of progress of cancer, or specimen collection conditions. 
     Furthermore, since the method of the present invention can concentrate a group in which the effects of an anti-EGFR antibody are high, and then can conduct detection, when compared with conventional methods based on gene expression, the present method can conduct higher-precision determination than conventional methods, even in therapeutic methods of using molecular targeted drugs. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  shows the results of the comprehensive DNA methylation analysis of 45 colorectal cancer cases having usage history of an anti-EGFR antibody drug (unsupervised hierarchical cluster analysis using 3163 probes having a standard deviation in β value distribution of greater than 0.25). 
         FIG. 2  shows a comparison between a highly-methylated group and a low-methylated group, in terms of (A) progression-free survival (PFS) and (B) overall survival (OS) when an anti-EGFR antibody drug has been used for the 45 colorectal cancer cases. 
         FIG. 3  shows the results of the comprehensive DNA methylation analysis of 52 colorectal cancer cases having usage history of an anti-EGFR antibody drug, which are different from the 45 cases in Example 1 (unsupervised hierarchical cluster analysis using 2577 probes having a standard deviation in β value distribution of greater than 0.25). 
         FIG. 4  shows a comparison between a highly-methylated group and a low-methylated group, in terms of (A) progression-free survival (PFS) and (B) overall survival (OS) when an anti-EGFR antibody drug has been used for the 52 colorectal cancer cases. 
         FIG. 5  shows the progression-free survival (PFS) upon the use of an anti-EGFR antibody drug: (A) a comparison between a highly-methylated group and a low-methylated group according to the present classification, and (B) a comparison between a mutant RAS group and a wild-type RAS group. 
         FIG. 6  shows the overall survival (OS) after completion of the initial administration of an anti-EGFR antibody drug: (A) a comparison between a highly-methylated group and a low-methylated group according to the present classification, and (B) a comparison between a mutant RAS group and a wild-type RAS group. 
         FIG. 7  shows the survival curve upon the use of an anti-EGFR antibody drug: (A) a comparison between a highly-methylated group and a low-methylated group according to the present classification, (B) a comparison among a highly-methylated group (HME), an intermediately-methylated group (IME) and a low-methylated group (LME) based on the classification of Yagi et al. 
         FIG. 8  shows the correlation of the progression-free survival (PFS) when a combination therapy comprising oxaliplatin (solid line) or a combination therapy comprising irinotecan (broken line) has been performed as a primary treatment on metastatic colorectal cancer, with methylation classification: (A) the results of the primary treatment of a highly-methylated (HMCC) group, and (B) the results of the primary treatment of a low-methylated (LMCC) group. 
         FIG. 9  shows the correlation of the progression-free survival (PFS) when a combination therapy comprising oxaliplatin (solid line) or a combination therapy comprising irinotecan (broken line) has been performed as a secondary treatment on metastatic colorectal cancer, with methylation classification: (A) the results of the secondary treatment of a highly-methylated (HMCC) group, and (B) the results of the secondary treatment of a low-methylated (LMCC) group. 
         FIG. 10  shows the correlation of the progression-free survival (PFS) when a combination therapy comprising oxaliplatin as a primary treatment and also comprising irinotecan as a secondary treatment (solid line), or a combination therapy comprising irinotecan as a primary treatment and also comprising oxaliplatin as a secondary treatment (broken line) has been performed on metastatic colorectal cancer, with methylation classification: (A) the treatment results of a highly-methylated (HMCC) group, and (B) the treatment results of a low-methylated (LMCC) group. 
         FIG. 11  shows the correlation of the overall survival (OS) when a combination therapy comprising oxaliplatin as a primary treatment and also comprising irinotecan as a secondary treatment (solid line), or a combination therapy comprising irinotecan as a primary treatment and also comprising oxaliplatin as a secondary treatment (broken line) has been performed on metastatic colorectal cancer, with methylation classification: (A) the treatment results of a highly-methylated (HMCC) group, and (B) the treatment results of a low-methylated (LMCC) group. 
         FIG. 12  shows the correlation of the progression-free survival (PFS) when a combination therapy comprising oxaliplatin (solid line) or a combination therapy comprising irinotecan (broken line) has been performed as a primary treatment on metastatic colorectal cancer, with CIMP classification: (A) the results of the primary treatment of a CIMP-positive group, and (B) the results of the primary treatment of a CIMP-negative group. 
         FIG. 13  shows the correlation of the progression-free survival (PFS) when a combination therapy comprising oxaliplatin (solid line) or a combination therapy comprising irinotecan (broken line) has been performed as a secondary treatment on metastatic colorectal cancer, with CIMP classification: (A) the results of the secondary treatment of a CIMP-positive group, and (B) the results of the secondary treatment of a CIMP-negative group. 
         FIG. 14  shows the correlation of the progression-free survival (PFS) when a combination therapy comprising oxaliplatin as a primary treatment and also comprising irinotecan as a secondary treatment (solid line), or a combination therapy comprising irinotecan as a primary treatment and also comprising oxaliplatin as a secondary treatment (broken line) has been performed on metastatic colorectal cancer, with CIMP classification: (A) the results of the primary treatment of a CIMP-positive group, and (B) the results of the primary treatment of a CIMP-negative group. 
         FIG. 15  shows the correlation of the overall survival (OS) with CIMP classification, when a combination therapy comprising oxaliplatin as a primary treatment and also comprising irinotecan as a secondary therapy (solid line), or a combination therapy comprising irinotecan as a primary treatment and also comprising oxaliplatin as a secondary treatment (broken line) has been performed on metastatic colorectal cancer: (A) the results of the primary treatment (oxaliplatin) of a CIMP-positive group, (B) the results of secondary treatment (oxaliplatin) of a CIMP-positive group, (C) the results of the primary/secondary therapies (oxaliplatin/irinotecan) of a CIMP-positive group, (D) the results of primary treatment (oxaliplatin) of a CIMP-negative group, (E) the results of the secondary treatment (oxaliplatin) of a CIMP-negative group, and (F) the results of primary/secondary therapies (oxaliplatin/irinotecan) of a CIMP-negative group. 
         FIG. 16  shows the procedures for narrowing probes in two cohorts and verification thereof (Example 7). 
         FIG. 17  shows the results obtained by classifying again 97 cases as analysis targets into an HMCC group and an LMCC group, using 24 markers (probes) that have been narrowed up by the analysis of the two cohorts. In the figure, the columns indicate individual cases (97 columns in total), and the red or blue color in the uppermost row shows that each case is classified into either HMCC or LMCC by the first analysis using 3144 or 2577 probes. The lines in the second row and so on (24 lines in total) indicate individual probes. The orange color shows that it has been determined that the case is methylation positive (=β value of 0.5 or greater), and the green color shows that it has been determined that the case is methylation negative (=β value of less than 0.5). 
     
    
    
     DESCRIPTION OF EMBODIMENTS 
     1. Definition 
     The present invention relates to a method for determining the responsiveness of a colorectal cancer patient to cancer drug therapy. Hereafter, the meanings of the terms used in the present invention and in the present description will be described. 
     In the present invention, the term “colorectal cancer” means a carcinoma developed in the large intestine (cecum, colon, and rectum), which includes carcinomas developed in the anal canal. The term “colorectal cancer patient” includes a subject who is suspected of having colorectal cancer and needs to examine the responsiveness to cancer drug therapy, as well as a subject who is affected with colorectal cancer. 
     The “cancer drug therapy” is not particularly limited, and examples of the cancer drug therapy include both a chemotherapy of using oxaliplatin, irinotecan and the like, and a therapy of using molecular targeted drugs such as an anti-EGFR antibody. 
     In the present invention, the term “anti-EGFR antibody” is used to mean an antibody specific to EGFR (epidermal growth factor receptor), or an immunologically active fragment thereof. Examples of such an anti-EGFR antibody include cetuximab that is a commercially available IgG 1 subclass human-mouse chimeric antibody, panitumumab that is an IgG 2 subclass completely human antibody, and further, all of anti-EGFR antibodies that are useful as molecular targeted drugs for cancer. 
     Approximately 80% of metastatic and/or recurrent colorectal cancers express EGFR, and the growth of cancer cells is suppressed by inhibiting the EGFR located most upstream of signaling with antibodies. However, there are cases where signaling is not inhibited even if the EGFR is blocked by antibodies. For example, as described above, it has been known that in the case of a patient having a mutation in K-RAS located downstream of a growth signaling pathway, signaling is not inhibited even by blocking EGFR. 
     In the present invention, the phrase “responsiveness to cancer drug therapy” means the responsiveness of a patient to cancer drug therapy, as described above. When the cancer drug therapy has effects on the patient, the patient is indicated to be “sensitive” to the therapy, and when the cancer drug therapy does not have effects on the patient, the patient is indicated to be “resistant” to the therapy. 
     The “specimen” used in the present invention is not particularly limited, as long as it contains a suspected lesion area isolated from a subject, namely, colorectal cancer cell-derived DNA (e.g., DNA derived from tumor in the plasma), such as colorectal cancer tissues or colorectal cancer cells. 
     The “DNA methylation” may occur at the carbon atom at position 5 of the pyrimidine ring of cytosine constituting DNA, or at the nitrogen atom at position 6 of the purine ring of adenine constituting DNA. In general, in the somatic tissues of an adult mammal, such DNA methylation occurs in a CpG site (i.e., a dinucleotide site in which cytosine is adjacent to guanine). In the case of cancer, hypermethylation is frequently observed in the CpG site, and particularly, in the CpG island in the promoter region. On the other hand, hypomethylation is also associated with progression of cancer. 
     The “DNA methylation” according to the present invention is not limited to the methylation of a CpG site, and it includes methylation of non-CpG sites, such as methylation regions in non-CpG sites known in human stem cells, and regions exhibiting different methylation between known normal cells and cancer cells. 
     The “level of DNA methylation” according to the present invention means the ratio of methylation (methylation/methylation+non-methylation), and for example, it is indicated with a β value. It is to be noted that such a β value is calculated by the following formula: 
       β value=(maximum value of fluorescence values of methylation-detecting probes)/(maximum value of fluorescence values of non-methylation-detecting probes+maximum value of fluorescence values of methylation-detecting probes+100)
 
     The “marker gene” used to measure the level of DNA methylation is not particularly limited. All genes contained in a specimen may be used as targets and may be comprehensively analyzed, or the targets may be limited to specific genes, and the specific genes may be then analyzed. The marker genes are preferably 4 or more genes selected from a group of genes having a significant difference in the β value between a highly-methylated group and a low-methylated group, and specifically, the present marker genes are selected from a group of 1,053 genes shown in Table 7 or a group of 24 genes shown in Table 8. For example, the marker genes include genes selected from the 7 genes indicated with the genetic symbols CACNA1G, LOX, SLC30A10, ELMO1, HAND1, IBN2 and THBD, or the 24 genes which are specified with the chromosome numbers and location information shown in Table 8. 
     2. Method for Determining Responsiveness to Cancer Drug Therapy 
     In the present invention, the responsiveness of a colorectal cancer patient to cancer drug therapy is determined based on the level of DNA methylation in a specimen containing a colorectal cancer tissue or colorectal cancer cells of the aforementioned patient. 
     The method of the present invention comprises, for example, the following steps: 
     (1) a step of measuring the level of DNA methylation in a specimen containing a colorectal cancer tissue, colorectal cancer cells, or colorectal cancer cell-derived DNA of a subject (measurement step),
 
(2) a step of defining a gene having a β value of 0.5 or more as methylation positive, and then, classifying the subject into a highly-methylated group when the ratio of a methylation-positive gene is 60% or more, and classifying the subject into a low-methylated group when the ratio of a methylation-positive gene is less than 60% (analysis and/or classification step), and
 
(3) a step of determining that the subject is sensitive to cancer drug therapy when the subject is classified into the low-methylated group, and determining that the subject is resistant to cancer drug therapy when the subject is classified into the highly-methylated group (determination step).
 
     2.1 Measurement Step 
     (1) Extraction of DNA 
     First, genomic DNA is extracted from a specimen isolated from a subject. DNA extraction may be carried out according to a method known in the present technical field. Such DNA extraction can be carried out, for example, using a commercially available kit (QIAamp DNA Micro Kit (QIAGEN), NucleoSpinR Tissue (TAKARA), etc.). 
     (2) Measurement of the Level of DNA Methylation 
     The measurement of the level of DNA methylation is not particularly limited, and examples of the measurement method include (A) an analysis method involving a bisulfite treatment and sequencing, (B) a method comprising fragmenting methylated DNA, concentrating it, and then analyzing the methylated DNA, (C) an analysis method of utilizing methylation-sensitive restriction enzymes, and (D) an analysis method of utilizing a methylation-specific PCR method. All of these methods may be applied. 
     As a preferred example, there is a method of using the bead arrays of Illumina (Infinium (registered trademark) Human Methylation 450 BeadChip). In this method, cytosine that has not been methylated in DNA (non-methylated cytosine) is converted to uracil by performing a bisulfite treatment, so that the methylated cytosine can be distinguished from the non-methylated cytosine. Thereafter, probes immobilized on two beads, namely, a methylation probe (type M) and a non-methylation probe (type U), which are specific to individual sites, are hybridized, and a single nucleotide elongation reaction is then carried out using labeled ddNTP, so that the ratio between methylation and non-methylation is calculated based on these fluorescence intensity signals. Thereby, a comprehensive DNA methylation analysis can be simply carried out. 
     Another example can be the MassARRAY method of Sequenom. In this method, DNA methylation is analyzed by utilizing a difference in masses caused by a difference in the nucleotide sequences of regions to be analyzed. Specifically, non-methylated cytosine is converted to uracil by treating DNA with bisulfite (wherein methylated cytosine is not converted), and the presence or absence of methylation is then analyzed based on a difference in the masses of the nucleotides G and A in the complementary strand thereof. Thereby, large quantities of samples can be quantitatively analyzed in a short time. 
     The level of DNA methylation may be measured for all genes contained in a specimen. However, the present inventors have found that the responsiveness of a subject to cancer drug therapy can be determined by measuring the methylation levels of specific genes. Such specific genes are 4 or more genes selected from a group of genes having a significant difference in the β value between a highly-methylated group and a low-methylated group, and specifically, such specific genes are selected from a group of 1,053 genes shown in Table 7 or a group of 24 genes shown in Table 8. For example, the marker genes include genes selected from the 7 genes indicated with the genetic symbols CACNA1G, LOX, SLC30A10, ELMO1, HAND1, IBN2 and THBD. Otherwise, the marker genes include genes selected from the 24 genes specified with the chromosome numbers and location information shown in Table 8. 
     By analyzing the methylation levels of 4 or more genes, preferably 4 to 7 genes, more preferably 4 to 20 genes, and further preferably 4 to 10 genes selected from the above described marker genes, the responsiveness of a subject to cancer drug therapy can be predicted. 
     2.2 Analysis and/or Classification Step 
     (1) Analysis of the Level of DNA Methylation 
     Subsequently, the above described measurement results are analyzed, and the subject is classified into either a highly-methylated group or a low-methylated group. The level of DNA methylation can be quantified, for example, using the aforementioned β value or the like. This β value is calculated and/or analyzed for all genes or the above described specific genes, so that the subject can be classified into either a highly-methylated group or a low-methylated group. 
     (2) Classification into Highly-Methylated Group or Low-Methylated Group 
     The subject may be classified into a highly-methylated group or a low-methylated group by performing the comparative analysis of the results of the subject with the profiles of the level of DNA methylation in a specimen that has been previously obtained from a colorectal cancer patient, or the subject may also be classified based on a predetermined cut-off value experimentally determined from accumulated data. 
     As described in the Examples of the present application, the present inventors have found that, when the aforementioned marker gene having a β value of 0.5 or more is defined as methylation positive, and in a case where the ratio of a methylation-positive gene is 60% or more, the subject can be classified into a highly-methylated group, and in a case where the ratio of a methylation-positive gene is less than 60%, the subject can be classified into a low-methylated group. According to this method, the subject can be simply classified into a highly-methylated group or a low-methylated group, based on the methylation levels of at least 4 marker genes. 
     2.3 Determination Step 
     Based on the above described classification results, when the subject is classified into a low-methylated group, it is determined that the subject is sensitive to cancer drug therapy, whereas when the subject classified into a highly-methylated group, it is determined that the subject is resistant to cancer drug therapy. 
     2.4 Application to Selection of Treatment 
     The method of the present invention can be applied to selection of chemotherapy for colorectal cancer, and in particular, for unresectable metastatic colorectal cancer, based on a difference in methylation states. That is to say, when a primary treatment is initiated, it is considered at present that both the regimen of an irinotecan-based chemotherapy and the regimen of an oxaliplatin-based chemotherapy may be available. However, by using the method of the present invention, it can be determined that a patient in a highly-methylated group should receive an irinotecan-based chemotherapy, and on the other hand, it can be determined that a patient in a highly-methylated group who has initiated to receive an irinotecan-based chemotherapy should receive an oxaliplatin-based chemotherapy as a secondary treatment. On the other hand, it can be determined that a patient in a low-methylated group may receive either an irinotecan-based chemotherapy or an oxaliplatin-based chemotherapy as a primary treatment. 
     In the method of the present invention, from among cases which have been classified into a treatment-sensitive group according to the previous reports, actually resistant cases can be extracted, so that it becomes possible to predict therapeutic effects with higher precision. Moreover, regardless of the state of progress of cancer or conditions for specimen collection, therapeutic effects can be precisely determined not only regarding chemotherapy, but also regarding therapies of using molecular targeted drugs such as an anti-EGFR antibody. 
     Furthermore, in the method of the present invention, a lower p value is found between a treatment-sensitive group and a treatment-resistant group, than in the case of classification based on expression arrays, and it is possible to concentrate a group having high therapeutic effects, so that determination can be carried out with higher precision. 
     Further, as described in the after-mentioned Examples, in the method of the present invention, two independent case groups having a significant difference in terms of response rate, progression-free survival (PFS: Progression-Free Survival), and overall survival (OS: Overall Survival) upon the use of an anti-EGFR antibody drug have been successfully extracted, and it has also been demonstrated that the present method is excellent in terms of reproducibility. 
     Regarding the guidelines for administration of an anti-EGFR antibody used as a therapeutic agent for metastatic colorectal cancer, a method of administering the present antibody only to patients with a wild-type KRAS gene has been recommended. The method of the present invention is based on an epigenetic method that is different from conventional genetic methods, and the present method is basically different from conventional methods in that the present method enables the extraction of patients having resistance to the present antibody from a group of patients who have been classified to be sensitive to the present antibody under the current administration guidelines. 
     3. Kit and/or Probe Set for Predicting Responsiveness to Cancer Drug Therapy 
     The present invention also provides a probe set and a kit for predicting the responsiveness of a colorectal cancer patient to cancer drug therapy. 
     The probe set of the present invention comprises a probe which comprises a sequence complementary to a region comprising the CpG site of at least one of 4 or more marker genes selected from the gene group shown in Table 7 or Table 8, and which is capable of detecting the presence or absence of the methylation of the CpG site. Herein, the presence or absence of methylation means a probe capable of detecting the cytosine in a methylation site and the uracil in a non-methylation site, in the case of bisulfite sequencing. It is to be noted that the above described marker genes preferably include one or more genes selected from CACNA1G, LOX, SLC30A10, ELMO1, HAND1, IBN2 and THBD. 
     The kit of the present invention comprises 
     (a) a probe which comprises a sequence complementary to a region comprising the CpG site of at least one of 4 or more marker genes selected from the gene group shown in Table 7 or Table 8, and which is capable of detecting the presence or absence of the methylation of the CpG site, and
 
(b) a primer pair which binds to a region comprising the CpG site of at least one of 4 or more marker genes selected from the gene group shown in Table 7 or Table 8, and which is capable of amplifying the region comprising the CpG region.
 
     It is to be noted that the above described marker genes preferably include one or more genes selected from the genetic symbols CACNA1G, LOX, SLC30A10, ELMO1, HAND1, IBN2 and THBD. Otherwise, the marker genes preferably include genes selected from the 24 genes specified with the chromosome numbers and location information shown in Table 8. 
     By using the probe set or kit of the present invention, the responsiveness of a colorectal cancer patient to cancer drug therapy can be simply and highly precisely predicted. 
     As described in the after-mentioned Examples, both the method based on expression arrays and the method of the present invention use comprehensive data to carry out an unsupervised hierarchical cluster analysis, thereby identifying subgroups having different drug sensitivity. However, the method of the present invention that is based on methylation analysis is considered to be a more practical invention because it has succeeded in identifying several probe sets capable of extracting two groups having a significant difference in drug sensitivity. 
     EXAMPLES 
     Hereinafter, the present invention will be described in more detail in the following Examples. However these Examples are not intended to limit the scope of the present invention. 
     Example 1: Comprehensive DNA Methylation Analysis of Using 45 Colorectal Cancer Cases 
     Using formalin-fixed paraffin-embedded tissues (FFPE specimen) of colorectal cancer tumor tissues that had been surgically excised from 45 colorectal cancer cases having usage history of an anti-EGFR antibody drug, a comprehensive DNA methylation analysis was carried out by employing Infinium 450K (Illumina). It is to be noted that the target cases were set to be cases in which no mutations were found in KRAS exon 2 according to a Sanger method. 
     The β value of each probe (methylated probes/methylated probes+non-methylated probes) was calculated, and thereafter, 3,163 probes having a standard deviation in the β value distribution that was greater than 0.25 were used to carry out an unsupervised hierarchical cluster analysis ( FIG. 1 ). 
     As a result of the above described analysis, the analysis target cases were classified into two groups, namely, a Highly-Methylated Colorectal Cancer (HMCC) group (17 cases) having a high methylation level and a Low-Methylated Colorectal Cancer (LMCC) group (28 cases) having a low methylation level. 
     The response rate to a high EGFR antibody drug was compared between the above described two groups (HMCC group and LMCC group) (Table 1). When the response rate to the anti-EGFR antibody drug has been focused, the response rate of the LMCC group was found to be 36% (10 cases), whereas the response rate of the HMCC group was found to be 6% (1 case). Thus, the response rate of the LMCC group was significantly high (p=0.03). 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Comparison of response rate to anti-EGFR antibody 
               
               
                 drug in Cohort 1 between two groups 
               
            
           
           
               
               
               
               
               
            
               
                   
                 All samples 
                 HMCC group 
                 LMCC group 
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Number of 
                   
                 Number of 
                   
                 Number of 
                   
                 p 
               
               
                   
                 subjects 
                 % 
                 subjects 
                 % 
                 subjects 
                 % 
                 value 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 RR (%) 
                   
                 25.0 
                   
                 6.3 
                   
                 35.7 
                 0.03 
               
               
                 CR 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 PR 
                 11 
                 25.0 
                 1 
                 6.3 
                 10 
                 35.7 
               
               
                 SD 
                 15 
                 34.1 
                 4 
                 25.0 
                 11 
                 39.3 
               
               
                 PD 
                 18 
                 40.9 
                 11 
                 68.8 
                 7 
                 25.0 
               
               
                 NA 
                 1 
                   
                 1 
                   
                 0 
               
               
                   
               
               
                 CR: complete response, 
               
               
                 PR: partial response, 
               
               
                 SD: stable, 
               
               
                 PD: progressed, 
               
               
                 RR: response rate 
               
            
           
         
       
     
     When the progression-free survival (PFS) upon the use of an anti-EGFR antibody drug was focused, the median of the LMCC group was found to be 197 days, whereas the median of the HMCC group was found to be 72 days. Thus, the progression-free survival (PFS) was significantly prolonged in the LMCC group (p≦0.001, HR=0.27:  FIG. 2A ). 
     With regard to a comparison in terms of the overall survival (OS) after completion of the initial administration of an anti-EGFR antibody drug, the median of the LMCC group was found to be 24.9 months, whereas the median of the HMCC group was found to be 5.6 months. Thus, the overall survival (OS) was significantly prolonged in the LMCC group (p≦0.001, HR=0.19:  FIG. 2B ). 
     From the aforementioned results, a significant difference was found in all of response rate, PFS, and OS, upon the use of an anti-EGFR antibody drug, between the two groups that had been classified based on the comprehensive DNA methylation analysis, and thus, it was strongly suggested that therapeutic effects could be predicted. 
     Example 2: Verification of Independent 52 Colorectal Cancer Cases 
     Using 52 colorectal cancer cases having usage history of an anti-EGFR antibody drug, which were independent from the 45 cases used in Example 1, a comprehensive DNA methylation analysis was carried out by employing Infinium 450K. As with Example 1, the target cases were set to be cases in which no mutations were found in KRAS exon 2 according to a Sanger method. 
     As with Example 1, the β value of each probe (methylated probes/methylated probes+non-methylated probes) was calculated, and thereafter, 2,577 probes having a standard deviation in the β value distribution that was greater than 0.25 were used to carry out an unsupervised hierarchical cluster analysis ( FIG. 3 ). 
     As a result of the above described analysis, the analysis target cases were classified into two groups, namely, an HMCC group (17 cases) having a high methylation level and an LMCC group (35 cases) having a low methylation level. 
     The response rate to a high EGFR antibody drug was compared between the above described two groups (HMCC group and LMCC group) (Table 2). When the response rate to the anti-EGFR antibody drug has been focused, the response rate of the LMCC group was found to be 34% (12 cases), whereas the response rate of the HMCC group was found to be 6% (1 case). Thus, the response rate of the LMCC group was significantly high (p=0.03). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Comparison of response rate to anti-EGFR antibody 
               
               
                 drug in Cohort 2 between two groups 
               
            
           
           
               
               
               
               
               
            
               
                   
                 All samples 
                 HMCC group 
                 LMCC group 
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Number of 
                   
                 Number of 
                   
                 Number of 
                   
                 p 
               
               
                   
                 subjects 
                 % 
                 subjects 
                 % 
                 subjects 
                 % 
                 value 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 RR (%) 
                   
                 25.0 
                   
                 5.9 
                   
                 34.3 
                 0.03 
               
               
                 CR 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 PR 
                 13 
                 25.0 
                 1 
                 5.9 
                 12 
                 34.3 
               
               
                 SD 
                 22 
                 42.3 
                 7 
                 41.2 
                 15 
                 42.9 
               
               
                 PD 
                 17 
                 32.7 
                 9 
                 52.9 
                 8 
                 22.9 
               
               
                 NA 
                 0 
                   
                 0 
                   
                 0 
               
               
                   
               
               
                 CR: complete response, 
               
               
                 PR: partial response, 
               
               
                 SD: stable, 
               
               
                 PD: progressed, 
               
               
                 RR: response rate 
               
            
           
         
       
     
     When the progression-free survival (PFS) upon the use of an anti-EGFR antibody drug was focused, the median of the LMCC group was found to be 191 days, whereas the median of the HMCC group was found to be 70 days. Thus, the progression-free survival (PFS) was significantly prolonged in the LMCC group (p=&lt;0.001, HR=0.22:  FIG. 4A ). 
     With regard to a comparison in terms of the overall survival (OS) after completion of the initial administration of an anti-EGFR antibody drug, the median of the LMCC group was found to be 14.1 months, whereas the median of the HMCC group was found to be 9.3 months. Thus, the overall survival (OS) was significantly prolonged in the LMCC group (p=0.03, HR=0.35:  FIG. 4B ). 
     From the aforementioned results, a significant difference was found in all of response rate, PFS, and OS, upon the use of an anti-EGFR antibody drug, between the two groups that had been classified based on the methylation state, and thus, the role of the comprehensive methylation state demonstrated in Example 1 as a factor for predicting the therapeutic effects of an anti-EGFR antibody drug was reproduced. 
     Example 3: Comparison with Existing Biomarkers 
     As described above, in recent years, it has been reported that an anti-EGFR antibody drug provides insufficient therapeutic effects on a case having mutations on KRAS exons 2, 3 and 4, NRAS exons 2, 3 and 4, as well as KRAS exon 2. Thus, the present antibody has been clinically applied as a biomarker in Japan these days. 
     Out of 97 analysis target cases in the present study, 49 cases were also subjected to whole exon analysis. Thus, in terms of prediction of the therapeutic effects of an anti-EGFR antibody drug, a comparison was made between the present classification based on methylation and classification using existing biomarkers (the aforementioned KRAS and NRAS are collectively referred to as a RAS genotype) (Table 3). 
     
       
         
           
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Comparison of response rate to anti-EGFR antibody drug between 
               
               
                 two groups based on present classification and RAS genotype 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Present classification 
               
            
           
           
               
               
               
               
            
               
                   
                 HMCC group (n = 13) 
                 LMCC group (n = 36) 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Number of 
                   
                 Number of 
                   
                   
               
               
                   
                 subjects 
                 % 
                 subjects 
                 % 
                 p value 
               
               
                   
               
               
                 RR (%) 
                   
                 7.7 
                   
                 33.3 
                 0.07 
               
               
                 CR 
                 0 
                 0 
                 0 
                 0 
               
               
                 PR 
                 1 
                 7.7 
                 12 
                 33.3 
               
               
                 SD 
                 7 
                 53.8 
                 16 
                 44.4 
               
               
                 PD 
                 5 
                 38.5 
                 8 
                 22.2 
               
               
                 NA 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 RAS genotype 
               
            
           
           
               
               
               
               
            
               
                   
                 mutant RAS group 
                 wild-type RAS group 
                   
               
               
                   
                 (n = 13) 
                 (n = 36) 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Number of 
                   
                 Number of 
                   
                   
               
               
                   
                 subjects 
                 % 
                 subjects 
                 % 
                 p value 
               
               
                   
               
               
                 RR (%) 
                   
                 7.7 
                   
                 33.3 
                 0.07 
               
               
                 CR 
                 0 
                 0 
                 0 
                 0 
               
               
                 PR 
                 1 
                 7.7 
                 12 
                 33.3 
               
               
                 SD 
                 5 
                 38.5 
                 18 
                 50.0 
               
               
                 PD 
                 7 
                 53.8 
                 6 
                 16.7 
               
               
                 NA 
                 0 
                   
                 0 
                 0 
               
               
                   
               
               
                 CR: complete response, 
               
               
                 PR: partial response, 
               
               
                 SD: stable, 
               
               
                 PD: progressed, 
               
               
                 RR: response rate 
               
            
           
         
       
     
     First, a comparison was made in terms of the response rate to the anti-EGFR antibody drug. Treatment-resistant groups, namely, an HMCC group and a mutant RAS group both had a response rate of 7.7%, and on the other hand, treatment-sensitive groups, namely, an LMCC group and a wild-type RAS group both had a response rate of 33.3%. From these results, it was demonstrated that the present classification exhibits a correlation with the response rate to the anti-EGFR antibody drug, at a level equivalent to the classification based on the RAS genotype. 
     Subsequently, in terms of the progression-free survival (PFS) upon the use of an anti-EGFR antibody drug, a comparison was made ( FIG. 5 ). In both of the classifications, PFS was significantly prolonged in the treatment-sensitive groups (LMCC group and wild-type RAS group). The hazard ratios (HR) were found to be 0.26 (LMCC group vs. HMCC group) and 0.32 (wild-type RAS group vs. mutant RAS group), respectively. From these results, it was demonstrated that the present classification exhibits a correlation with PFS upon the use of the anti-EGFR antibody drug, at a level equivalent to the classification based on the RAS genotype. 
     A multivariate analysis was carried out using factors possibly having an influence on the progression-free survival (PFS) upon the use of an anti-EGFR antibody drug (Table 4). The hazard ratio (HR) of the present classification based on the methylation state, in which the p value was lower than 0.05, was equivalent to the hazard ratio (HR) of the classification based on RAS genotype, in which the p value was lower than 0.05. From these results, it was demonstrated that the present classification is an independent determinant for the PFS upon the use of the anti-EGFR antibody drug, and also that the hazard ratio of the present classification is equivalent to that of the classification based on the RAS genotype. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Multivariate analysis of using Cox proportional hazard 
               
               
                 models on PFS upon use of anti-EGFR antibody drug 
               
            
           
           
               
               
               
            
               
                   
                 HR 
                 P-value 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                 Methylation state (HMCC group vs. LMCC group) 
                 0.36 
                 0.03 
               
               
                 RAS genotype (mutant group vs. wild-type group) 
                 0.36 
                 0.02 
               
               
                 Age (less than 61 years old vs. 61 years old or more) 
                 0.81 
                 0.55 
               
               
                 Sex (male vs. female) 
                 0.94 
                 0.88 
               
               
                 Primary site (distal colon vs. proximal colon) 
                 1.36 
                 0.46 
               
               
                 Clinical stage upon excision of primary lesion (stage III 
                 0.75 
                 0.40 
               
               
                 or lower vs. stage IV) 
               
               
                 Number or organs having metastasis (1 or less vs. 2 or 
                 1.36 
                 0.37 
               
               
                 more) 
               
               
                 Number of previous regimens (2 or less vs. 3 or more) 
                 1.25 
                 0.72 
               
               
                 BRAF mutation (without vs. with) 
                 0.17 
                 0.07 
               
               
                   
               
            
           
         
       
     
     In terms of the overall survival (OS) after completion of the initial administration of an anti-EGFR antibody drug, a comparison was made ( FIG. 6 ). In both of the two classifications, OS tended to be prolonged in treatment-sensitive groups (LMCC group and wild-type RAS group). The hazard ratios (HR) were found to be 0.42 (LMCC group vs. HMCC group) and 0.39 (wild-type RAS group vs. mutant RAS group). In both of the classification methods, a significant difference was not found between the two groups. However, the present classification exhibited a correlation even with OS after completion of the initial administration of the anti-EGFR antibody drug, at a level equivalent to the classification based on the RAS genotype. 
     As described above, the present classification exhibited a correlation with all of the response rate to an anti-EGFR antibody drug, PFS upon the use of an anti-EGFR antibody drug, and OS after completion of the initial administration of an anti-EGFR antibody drug, at levels equivalent to the classification based on the RAS genotype. Moreover, from the results of the multivariate analysis, it was found that the present classification is a determinant independent from the RAS genotype, with regard to PFS upon the use of an anti-EGFR antibody drug. 
     Example 4: Comparison with Known Subtype Classification 
     Yagi et al. have classified colorectal cancer into three subtypes ((HME (highly-methylated group), IME (intermediately-methylated group), and LME (low-methylated group)) by examining the methylation states of 7 genes, and have then demonstrated that cases having a KRAS mutation are concentrated in IME (cited above: Yagi K. et al., Clin Cancer Res. 2010 Jan. 1; 16(1): 21-33). Moreover, Yagi et al. have also demonstrated that the overall survival is significantly reduced in cases having IME and a KRAS mutation, in compared with other case groups. 
     These 7 genes were evaluated in terms of methylation states in our case groups, and the genes were then classified into the three groups in accordance with the method described in the aforementioned study paper. 
     From 6 out of the 7 genes used in the subtype classification, probes contained in the region analyzed by Yagi et al. were extracted. However, in the case of the remaining one gene (FBN2), since probes contained in the region evaluated by Yagi et al. had not been designed, probes that were located close to the region evaluated by Yagi et al. were extracted from probes contained in the same CpG island, using the browser of UCSC. 
     A plurality of probes were extracted from each marker. Thus, when there were, for example, 3 probes, if a majority (two or more) of probes was found to be methylated (β value≧0.5), the marker was considered positive to methylation. 
     As a result, a total of 97 cases from Example 1 and Example 2 were classified into 3 groups, namely, into HME (7 cases), IME (16 cases) and LME (74 cases) (Table 5). 
     
       
         
           
               
             
               
                 TABLE 5 
               
               
                   
               
               
                 Comparison of response rate to anti- 
               
               
                 EGFR antibody between two groups 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Present classification 
               
            
           
           
               
               
               
               
            
               
                   
                 HMCC 
                 LMCC 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Number of 
                   
                 Number of 
                   
                   
               
               
                   
                 subjects 
                 % 
                 subjects 
                 % 
                 p value 
               
               
                   
               
               
                 RR (%) 
                   
                 6.1 
                   
                 34.9 
                 0.002 
               
               
                 CR 
                 0 
                 0 
                 0 
                 0 
               
               
                 PR 
                 2 
                 6.1 
                 22 
                 34.9 
               
               
                 SD 
                 11 
                 33.3 
                 26 
                 41.3 
               
               
                 PD 
                 20 
                 60.6 
                 15 
                 23.8 
               
               
                 NA 
                 1 
                   
                 0 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Yagi classification 
               
            
           
           
               
               
               
               
            
               
                   
                 HME + IME 
                 LME 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Number of 
                   
                 Number of 
                   
                   
               
               
                   
                 subjects 
                 % 
                 subjects 
                 % 
                 p value 
               
               
                   
               
               
                 RR (%) 
                   
                 4.5 
                   
                 31.1 
                 0.01 
               
               
                 CR 
                 0 
                 0 
                 0 
                 0 
               
               
                 PR 
                 1 
                 4.5 
                 23 
                 31.1 
               
               
                 SD 
                 7 
                 31.8 
                 30 
                 40.5 
               
               
                 PD 
                 14 
                 63.6 
                 21 
                 28.4 
               
               
                 NA 
                 1 
                   
                 0 
                 0 
               
               
                   
               
               
                 CR: complete response, 
               
               
                 PR: partial response, 
               
               
                 SD: stable, 
               
               
                 PD: progressed, 
               
               
                 RR: response rate 
               
            
           
         
       
     
     The median of the progression-free survival (PFS) upon the use of an anti-EGFR antibody drug was 85 days in HME, 67 days in IME, and 168 days in LME. Thus, the results demonstrated that the progression-free survival (PFS) was significantly prolonged in LME, in comparison to the two other groups HME and IME (vs. HME, p=0.004, vs. IME, p=1.14E-06, vs. HME+IME, p=3.21E-07:  FIG. 7B ). 
     From the aforementioned results, it was demonstrated that it is sufficiently possible to predict the therapeutic effects of an anti-EGFR antibody drug based on methylation profiles, even by narrowing the number of used probes to several probes, and it was also demonstrated that the conventional diagnostic method based on comprehensive analysis can be converted to a simple diagnostic method involving detection of methylation in a limited region, which is ready for practical use. 
     In addition, 23 cases included in HME and IME were all included in the highly-methylated group in Examples 1 and 2. 
     The present Example demonstrated that the classification method of the present invention can extract many methylated cases, in comparison to the existing subtype classification based on methylation, and that even some highly-methylated cases, which could not be extracted by the existing subtype classification, are shown to be resistant to the anti-EGFR antibody drug. That is to say, according to the method of the present invention, therapeutic sensitivity to the anti-EGFR antibody drug can be predicted with higher precision than that of the existing subtype classification. 
     There are a total of 34 highly-methylated group cases that are drug resistant groups in Examples 1 and 2. It was considered that 11 cases, which may be drug resistant cases included in LME, can be extracted by adding some more markers to the markers associated with the 7 genes used in Example 3. 
     Example 5: Studies Regarding Classification Method Using a Limited Number of Probes 
     Using 97 cases included in Example 1 and Example 2, a classification method using a limited number of probes was studied. In Examples 1 and 2, the extracted 3,163 and 2,577 probes were used in each analysis, and the target cases were classified according to an unsupervised cluster analysis. Among the probes used in the analysis in each Example, 1,744 probes were common in Examples 1 and 2. From these 1,744 probes, 1,053 probes having a difference in the β value between the case group classified into the HMCC group and the case group classified into the LMCC group were extracted (Table 7: shown at the end of the Examples). 
     From the thus extracted 1,053 probes, 4 to 10 probes were randomly extracted, and the cases were then classified into an HMCC group or an LMCC group, depending on the methylation states of the extracted probes. With regard to determination of the methylation of each probe, when the probe had a β value of 0.5 or greater, it was determined that the probe was positive to methylation, and when the probe had a β value of less than 0.5, it was determined that the probe was negative to methylation. 
     When 60% or more of the probes used in the analysis were methylation-positive, the case was classified into an HMCC group (for example, the case is classified into an HMCC group, if 3 or more of the used 4 probes are methylation-positive, or 4 or more of the used 6 probes are methylation-positive). 
     Regarding the results classified by the above described method, the classification results of each case in Examples 1 and 2 were assumed to be correct, and sensitivity and specificity were calculated. Specifically, the sensitivity indicates the ratio of the cases considered to be among an HMCC group also by the method of the present Example to a total of 34 cases considered to be among an HMCC group in Examples 1 and 2. On the other hand, the specificity indicates the ratio of the cases considered to be among an LMCC group also by the method of Example 5 to a total of 63 cases considered to be among an LMCC group in Examples 1 and 2. 
     As the number of probes extracted, five numbers were set (4, 5, 6, 7, and 10). Extraction of any given probes, classification of cases, and calculation of sensitivity and specificity were defined as 1 set, and 5 sets of these operations were repeatedly carried out under individual conditions, and the mean value thereof was then defined as sensitivity or specificity under individual conditions. The sensitivity and specificity calculated under individual conditions are shown in the following table. 
     
       
         
           
               
               
               
               
               
               
             
               
                   
                 TABLE 6 
               
               
                   
                   
               
               
                   
                 4_3 
                 5_3 
                 6_4 
                 7_5 
                 10_6 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Sensitivity 
                 83.54% 
                   90% 
                 87.06% 
                 83.52% 
                 90.12% 
               
               
                 Specificity 
                 93.66% 
                 90.80% 
                 91.78% 
                 97.12% 
                 95.26% 
               
               
                   
               
            
           
         
       
     
     The numbers shown in the form of X_Y in the uppermost row of each column indicate determination conditions. That is, the numbers X_Y indicate that, among the randomly extracted X probes, a Y number or more of probes are methylation-positive (e.g.: “4_3” indicates that 3 or more of the extracted 4 probes are methylation-positive). 
     From these results, it was demonstrated that a case group can be classified with sensitivity of 83.5% and specificity of 93.7%, by randomly extracting at least 4 probes from a list of the extracted 1,053 probes. 
     From the above described results, it was demonstrated that the therapeutic effects of an anti-EGFR antibody drug can be more simply predicted with sensitivity and specificity sufficiently suitable for practical use, by evaluating the methylation states of several probes selected from the list of 1,053 probes shown in Table 7. 
     Example 6: Correlation of Treatment Results with Methylation Classification in Metastatic Colorectal Cancer 
     1) Correlation of the Results of Primary Treatment with Methylation Classification 
     A comprehensive methylation analysis was carried out on 94 metastatic colorectal cancer cases according to Example 1, and the cases were classified into an HMCC group (34 cases) and an LMCC group (60 cases). The two groups were compared with each other in terms of progression-free survival after a primary treatment. 
     As a result, in the HMCC group, the progression-free survival tended to be shorter in the case of a combination therapy comprising oxaliplatin (solid line) than in the case of a combination therapy comprising irinotecan (broken line), and on the other hand, in the LMCC group, such a difference in the progression-free survival was not found between the two therapies ( FIG. 8 ). Accordingly, the methylation classification of the present invention was considered to be useful as a biomarker for selection of treatment in the primary treatment for metastatic colorectal cancer. 
     2) Correlation of the Results of Secondary Treatment with Methylation Classification 
     A comprehensive methylation analysis was carried out on 84 metastatic colorectal cancer cases, and the cases were classified into an HMCC group (31 cases) and an LMCC group (53 cases). Then, the two groups were compared with each other in terms of progression-free survival after a secondary treatment. 
     As a result, in the HMCC group, the progression-free survival tended to be shorter in the case of a combination therapy comprising irinotecan (broken line) than in the case of a combination therapy comprising oxaliplatin (solid line), and on the other hand, in the LMCC group, the progression-free survival tended to be shorter in the case of a combination therapy comprising oxaliplatin (solid line) than in the case of a combination therapy comprising irinotecan (broken line) ( FIG. 9 ). From the aforementioned results, the methylation classification of the present invention was considered to be useful as a biomarker for selection of treatment in the secondary treatment for metastatic colorectal cancer. 
     3) Correlation of the Results of the Primary and Secondary Therapies with Methylation Classification 
     A comprehensive methylation analysis was carried out on 84 metastatic colorectal cancer cases, and the cases were classified into an HMCC group (31 cases) and an LMCC group (53 cases). Then, the two groups were compared with each other in terms of the treatment results of a combination therapy comprising oxaliplatin or irinotecan in the primary and secondary therapies, and the overall survival. 
     As a result, in the HMCC group, the progression-free survival tended to be shorter in a group (solid line) on which a combination therapy comprising oxaliplatin was carried out as a primary treatment and also comprising irinotecan was then carried out as a secondary treatment, than in a group (broken line) on which the therapies were carried out in the opposite order ( FIG. 10A ). On the other hand, in the LMCC group, a difference in the progression-free survival was not found between the two therapies ( FIG. 10B ). 
     Moreover, in the HMCC group, the overall survival was significantly shorter in a group (solid line) on which a combination therapy comprising oxaliplatin was carried out as a primary treatment and also comprising irinotecan was then carried out as a secondary treatment, than in a group (broken line) on which the therapies were carried out in the opposite order ( FIG. 11A ). On the other hand, in the LMCC group, a difference in the overall survival was not found between the two therapies ( FIG. 11B ). 
     As described above, the present methylation classification was considered to be useful as a biomarker, not only for selection of treatment in the primary treatment and the secondary treatment for metastatic colorectal cancer, but also for selecting the order in which the primary treatment and the secondary treatment were applied. 
     Example 7: Correlation of Treatment Results with CIMP Classification in Metastatic Colorectal Cancer 
     1) Correlation of the Results of Primary Treatment with CIMP Classification 
     A CIMP analysis was carried out on 108 metastatic colorectal cancer cases according to a known method, and the cases were classified into a CIMP-positive group (24 cases) and a CIMP-negative group (84 cases). Then, the two groups were compared with each other in terms of progression-free survival after a primary treatment. 
     In the CIMP-positive group, the progression-free survival tended to be shorter in the case of a combination therapy comprising oxaliplatin (solid line) than in the case of a combination therapy comprising irinotecan (broken line). On the other hand, in the CIMP-negative group, a difference in the progression-free survival was not found between the two therapies ( FIG. 12 ). Accordingly, the CIMP classification was considered to be useful as a biomarker for selection of treatment in the primary treatment for metastatic colorectal cancer. 
     2) Correlation of the Results of Secondary Treatment with CIMP Classification 
     A CIMP analysis was carried out on 78 metastatic colorectal cancer cases, and the cases were classified into a CIMP-positive group (17 cases) and a CIMP-negative group (61 cases). Then, the two groups were compared with each other in terms of progression-free survival after a secondary treatment. 
     As a result, in the CIMP-positive group, the progression-free survival tended to be shorter in the case of a combination therapy comprising irinotecan (solid line) than in the case of a combination therapy comprising oxaliplatin (broken line) ( FIG. 13A ). On the other hand, in the CIMP-negative group, a difference in the progression-free survival was not found between the two therapies ( FIG. 13B ). Accordingly, the CIMP classification was considered to be useful as a biomarker for selection of treatment in the secondary treatment for metastatic colorectal cancer. 
     3) Correlation of the Results of Primary and Secondary Therapies with CIMP Classification 
     A CIMP analysis was carried out on metastatic colorectal cancer (78 cases), and the cases were classified into a CIMP-positive group (17 cases) and a CIMP-negative group (61 cases). Then, the two groups were compared with each other in terms of the treatment results of a combination therapy comprising oxaliplatin or irinotecan in the primary and secondary therapies. 
     As a result, in the CIMP-positive group, the progression-free survival was significantly shorter in a group (solid line) on which a combination therapy comprising oxaliplatin was carried out as a primary treatment and also comprising irinotecan was then carried out as a secondary treatment, than in a group (broken line) on which the therapies were carried out in the opposite order ( FIG. 14A ). On the other hand, in the CIMP-negative group, a difference in the progression-free survival was not found between the two therapies ( FIG. 14B ). 
     A CIMP analysis was carried out on 108 metastatic colorectal cancer cases on which a primary treatment had been carried out, and also on 78 metastatic colorectal cancer cases which had been subjected to a secondary treatment. Thus, the 108 cases were classified into a CIMP-positive group (24 cases) and a CIMP-negative group (84 cases), and the 78 cases were classified into a CIMP-positive group (17 cases) and a CIMP-negative group (61 cases). 
     In the CIMP-positive cases, the progression-free survival tended to be short in a group on which a combination therapy comprising oxaliplatin was carried out as a primary treatment and also comprising irinotecan was then carried out as a secondary treatment ( FIGS. 15A  and C). Meanwhile, when the analysis was continuously carried out from the primary treatment to the secondary treatment, it was found that the progression-free survival was significantly shorter in a group on which a combination therapy comprising oxaliplatin was carried out as a primary treatment and also comprising irinotecan was then carried out as the subsequent secondary treatment, than in a group on which the therapies were carried out in the opposite order ( FIG. 15E ). In the CIMP-negative group, a difference in the progression-free survival was not found between the two therapies ( FIGS. 15B , D and F). 
     As described above, the CIMP classification was also considered to be useful as a biomarker, not only for selection of treatment in the primary treatment and the secondary treatment for metastatic colorectal cancer, but also for selecting the order in which the primary treatment and the secondary treatment were applied. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 7 
               
               
                   
               
               
                 TargetID 
                 CHR 
                 MAPINFO 
                 UCSC_REFGENE_NAME 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 cg00024472 
                 17 
                 47573864 
                 NGFR 
               
               
                 cg00181968 
                 1 
                 179712204 
                 FAM163A 
               
               
                 cg00263760 
                 10 
                 118897366 
                 VAX1; VAX1 
               
               
                 cg00268840 
                 11 
                 44332653 
                 ALX4 
               
               
                 cg00278028 
                 22 
                 28196834 
                 MN1; MN1 
               
               
                 cg00281842 
                 5 
                 140855562 
                 PCDHGA4; PCDHGA12; PCDHGA11; PCDHGA11; PCDHGA9; 
               
               
                   
                   
                   
                 PCDHGA1; PCDHGB1; PCDHGC3; PCDHGB6; PCDHGB3; 
               
               
                   
                   
                   
                 PCDHGB7; PCDHGC3; PCDHGA6; PCDHGA8; PCDHGA10; 
               
               
                   
                   
                   
                 PCDHGA5; PCDHGB4; PCDHGA3; PCDHGC3; PCDHGA2; 
               
               
                   
                   
                   
                 PCDHGA7; PCDHGB2; PCDHGB5 
               
               
                 cg00290506 
                 1 
                 224804226 
                 CNIH3; CNIH3 
               
               
                 cg00295794 
                 13 
                 100641409 
               
               
                 cg00366818 
                 10 
                 28287879 
                 ARMC4 
               
               
                 cg00393798 
                 11 
                 8615694 
                 STK33 
               
               
                 cg00405843 
                 7 
                 128828575 
                 SMO 
               
               
                 cg00433770 
                 19 
                 17392656 
                 ANKLE1; ANKLE1 
               
               
                 cg00450824 
                 11 
                 8615685 
                 STK33 
               
               
                 cg00462168 
                 15 
                 79724794 
                 KIAA1024 
               
               
                 cg00498155 
                 19 
                 37157879 
                 ZNF461 
               
               
                 cg00500564 
                 10 
                 128994030 
                 FAM196A; DOCK1 
               
               
                 cg00513060 
                 19 
                 58111480 
                 ZKF530 
               
               
                 cg00544449 
                 15 
                 79724802 
                 KIAA1024 
               
               
                 cg00563873 
                 8 
                 93115461 
               
               
                 cg00592781 
                 12 
                 66122874 
               
               
                 cg00652796 
                 3 
                 96532832 
                 EPHA6 
               
               
                 cg00660608 
                 10 
                 125853219 
               
               
                 cg00662647 
                 1 
                 234350051 
                 SLC35F3 
               
               
                 cg00714184 
                 4 
                 155664242 
                 LRAT 
               
               
                 cg00755058 
                 13 
                 96296844 
                 DZIP1; DZIP1; DZIP1; DZIP1 
               
               
                 cg00765312 
                 12 
                 85674694 
                 ALX1 
               
               
                 cg00790098 
                 2 
                 223167400 
                 CCDC140 
               
               
                 cg00810956 
                 3 
                 27771766 
               
               
                 cg00866976 
                 16 
                 58224782 
                 GNAO1; GNAO1; LOC283856 
               
               
                 cg00880018 
                 13 
                 43149171 
                 TNFSF11; TNFSF11 
               
               
                 cg00881552 
                 14 
                 90527990 
                 KCNK13 
               
               
                 cg00912625 
                 3 
                 2140977 
                 CNTN4 
               
               
                 cg00922781 
                 10 
                 128077080 
                 ADAM12; ADAM12; ADAM12; ADAM12 
               
               
                 cg00945293 
                 1 
                 2984869 
                 FLJ42875; PRDM16; PRDM16; FLJ42875 
               
               
                 cg00962913 
                 1 
                 179712281 
                 FAM163A 
               
               
                 cg00973653 
                 1 
                 70033627 
               
               
                 cg00981837 
                 5 
                 33936262 
                 RXFP3 
               
               
                 cg00995327 
                 3 
                 142838847 
                 CHST2; CHST2 
               
               
                 cg01036409 
                 17 
                 66597372 
                 FAM20A 
               
               
                 cg01043019 
                 6 
                 127440510 
                 RSPO3 
               
               
                 cg01051310 
                 1 
                 228194443 
                 WNT3A 
               
               
                 cg01084239 
                 11 
                 8102510 
                 TUB; TUB 
               
               
                 cg01086895 
                 11 
                 6676515 
                 DCHS1 
               
               
                 cg01088410 
                 5 
                 170739179 
               
               
                 cg01163842 
                 14 
                 95235125 
                 GSC 
               
               
                 cg01188592 
                 20 
                 982831 
                 RSPO4; RSPO4; RSPO4; RSPO4 
               
               
                 cg01193217 
                 8 
                 145104575 
               
               
                 cg01229798 
                 10 
                 88126853 
                 GRID1 
               
               
                 cg01261798 
                 10 
                 134000034 
                 DPYSL4 
               
               
                 cg01277542 
                 16 
                 55689901 
                 SLC6A2 
               
               
                 cg01295203 
                 8 
                 70984199 
                 PRDM14 
               
               
                 cg01366595 
                 5 
                 42952307 
               
               
                 cg01379240 
                 3 
                 138666144 
                 C3orf72; FOXL2; C3orf72 
               
               
                 cg01454215 
                 2 
                 27530363 
                 UCN 
               
               
                 cg01545587 
                 14 
                 105993579 
                 TMEM121 
               
               
                 cg01555431 
                 6 
                 151562026 
                 AKAP12 
               
               
                 cg01559617 
                 1 
                 107684059 
                 NTNG1; NTNG1; NTNG1 
               
               
                 cg01616178 
                 8 
                 41755140 
                 ANK1 
               
               
                 cg01649597 
                 2 
                 232395061 
                 NMUR1 
               
               
                 cg01663018 
                 15 
                 53097777 
               
               
                 cg01705052 
                 16 
                 12996234 
                 SHISA9; SHISA9 
               
               
                 cg01718447 
                 7 
                 30722327 
                 CRHR2 
               
               
                 cg01783070 
                 20 
                 21686293 
                 PAX1 
               
               
                 cg01791410 
                 3 
                 150802997 
               
               
                 cg01802453 
                 4 
                 183370148 
                 ODZ3 
               
               
                 cg01826863 
                 2 
                 47797953 
                 KCNK12 
               
               
                 cg01886556 
                 4 
                 17783205 
                 FAM184B 
               
               
                 cg01923218 
                 11 
                 93063888 
                 CCDC67; CCDC67 
               
               
                 cg01950845 
                 15 
                 93632730 
                 RGMA; RGMA 
               
               
                 cg01956420 
                 13 
                 110959668 
                 COL4A1; COL4A2; COL4A2 
               
               
                 cg01963134 
                 12 
                 39299364 
                 CPNE8; CPNE8 
               
               
                 cg01969910 
                 3 
                 179169571 
                 GNB4 
               
               
                 cg01995480 
                 22 
                 45405827 
                 PHF21B; PHF21B 
               
               
                 cg02002231 
                 4 
                 81187798 
                 FGF5; FGF5; FGF5; FGF5 
               
               
                 cg02009088 
                 5 
                 139228153 
                 NRG2; NRG2; NRG2; NRG2 
               
               
                 cg02012576 
                 12 
                 133485691 
               
               
                 cg02040433 
                 16 
                 58497815 
                 NDRG4; NDRG4; NDRG4 
               
               
                 cg02055132 
                 3 
                 96533295 
                 EPHA6 
               
               
                 cg02071076 
                 4 
                 184827086 
                 STOX2; STOX2 
               
               
                 cg02146001 
                 20 
                 61051548 
                 GATA5 
               
               
                 cg02164129 
                 5 
                 76926550 
                 OTP 
               
               
                 cg02167438 
                 20 
                 9819697 
                 PAK7; PAK7 
               
               
                 cg02173749 
                 2 
                 121104029 
                 INHBB 
               
               
                 cg02182210 
                 20 
                 30619096 
                 C20orf160 
               
               
                 cg02229993 
                 1 
                 166134699 
                 FAM78B 
               
               
                 cg02230017 
                 16 
                 6069019 
                 A2BP1; A2BP1 
               
               
                 cg02246645 
                 12 
                 103352235 
                 ASCL1 
               
               
                 cg02269161 
                 11 
                 7273154 
                 SYT9 
               
               
                 cg02282626 
                 6 
                 30227363 
                 HLA-L 
               
               
                 cg02293118 
                 7 
                 44349704 
                 CAMK2B; CAMK2B; CAMK2B; CAMK2B; 
               
               
                   
                   
                   
                 CAMK2B; CAMK2B; CAMK2B; CAMK2B 
               
               
                 cg02305377 
                 12 
                 103355958 
               
               
                 cg02325324 
                 13 
                 23489846 
               
               
                 cg02329935 
                 5 
                 76506492 
                 PDE8B; PDE8B; PDE8B; PDE8B; PDE8B 
               
               
                 cg02330121 
                 6 
                 118228514 
                 SLC35F1 
               
               
                 cg02367930 
                 21 
                 32930938 
                 TIAM1 
               
               
                 cg02401454 
                 16 
                 230343 
                 HBQ1; HBQ1 
               
               
                 cg02403395 
                 3 
                 192445500 
                 FGF12 
               
               
                 cg02467990 
                 7 
                 49813102 
                 VWC2 
               
               
                 cg02483484 
                 1 
                 4716537 
                 AJAP1; AJAP1 
               
               
                 cg02484469 
                 20 
                 61051036 
                 GATA5 
               
               
                 cg02504416 
                 11 
                 44331629 
                 ALX4; ALX4 
               
               
                 cg02583418 
                 2 
                 105473340 
                 POU3F3 
               
               
                 cg02626129 
                 13 
                 31480646 
                 C13orf33; C13orf33 
               
               
                 cg02678084 
                 16 
                 4588491 
                 C16orf5 
               
               
                 cg02764245 
                 2 
                 66803033 
               
               
                 cg02788400 
                 13 
                 96296983 
                 DZIP1; DZIP1 
               
               
                 cg02860282 
                 1 
                 70033624 
               
               
                 cg02899206 
                 10 
                 1779835 
                 ADARB2 
               
               
                 cg02907374 
                 11 
                 15095028 
                 CALCB 
               
               
                 cg02916312 
                 6 
                 72596135 
                 RIMS1 
               
               
                 cg02948476 
                 14 
                 95235026 
                 GSC 
               
               
                 cg02952008 
                 1 
                 228604065 
                 TRIM17; TRIM17; TRIM17; TRIM17 
               
               
                 cg02979001 
                 14 
                 105310421 
               
               
                 cg02989521 
                 11 
                 107462437 
                 ELMOD1; LOC643923; ELMOD1 
               
               
                 cg03002846 
                 10 
                 135050343 
                 VENTX 
               
               
                 cg03011535 
                 20 
                 42544794 
                 TOX2; TOX2; TOX2; TOX2; TOX2 
               
               
                 cg03018796 
                 22 
                 37730664 
               
               
                 cg03020810 
                 10 
                 102890984 
                 TLX1; TLX1NB 
               
               
                 cg03030717 
                 12 
                 65218069 
               
               
                 cg03052869 
                 10 
                 88126299 
                 GRID1 
               
               
                 cg0305913l 
                 15 
                 60296996 
                 FOXB1 
               
               
                 cg03084724 
                 10 
                 125853232 
               
               
                 cg03129384 
                 10 
                 128994644 
                 FAM196A; DOCK1 
               
               
                 cg03157531 
                 10 
                 133795006 
                 BNIP3 
               
               
                 cg03168582 
                 9 
                 841850 
                 DMRT1 
               
               
                 cg03203223 
                 7 
                 103630549 
                 RELN; RELN 
               
               
                 cg03238797 
                 16 
                 77468893 
                 ADAMTS18; ADAMTS18 
               
               
                 cg03242819 
                 10 
                 128994432 
                 DOCK1; FAM196A 
               
               
                 cg03278146 
                 18 
                 5197327 
                 LOC642597 
               
               
                 cg03292388 
                 4 
                 8594514 
                 CPZ; CPZ; CPZ; CPZ; CPZ; CPZ 
               
               
                 cg03306374 
                 16 
                 23847325 
                 PRKCB; PRKCB; PRKCB; PRKCB 
               
               
                 cg03306486 
                 19 
                 1467952 
                 APC2 
               
               
                 cg03323292 
                 11 
                 134146132 
                 GLB1L3 
               
               
                 cg03356747 
                 10 
                 88126089 
                 GRID1 
               
               
                 cg03361585 
                 20 
                 47444241 
                 PREX1 
               
               
                 cg03370738 
                 10 
                 88126104 
                 GRID1 
               
               
                 cg03394150 
                 16 
                 28074384 
                 GSG1L 
               
               
                 cg03401096 
                 11 
                 123301171 
               
               
                 cg03405315 
                 11 
                 8615737 
                 STK33 
               
               
                 cg03437186 
                 7 
                 45614848 
                 ADCY1 
               
               
                 cg03509412 
                 12 
                 65515021 
                 WIF1; WIF1 
               
               
                 cg03559682 
                 11 
                 6439864 
                 APBB1; APBB1 
               
               
                 cg03562044 
                 19 
                 15342749 
                 EPHX3; EPHX3 
               
               
                 cg03603214 
                 1 
                 49242757 
                 AGBL4; BEND5 
               
               
                 cg03606772 
                 1 
                 152487856 
                 CRCT1 
               
               
                 cg03611452 
                 19 
                 38183253 
                 ZNF781 
               
               
                 cg03625010 
                 12 
                 24715484 
                 SOX5 
               
               
                 cg03699182 
                 2 
                 121104187 
                 INHBB 
               
               
                 cg03711182 
                 15 
                 79383924 
                 RASGRF1; RASGRF1 
               
               
                 cg03735496 
                 18 
                 18822637 
                 GREB1L 
               
               
                 cg03735888 
                 19 
                 58951602 
                 ZNF132 
               
               
                 cg03780132 
                 5 
                 42951346 
               
               
                 cg03825010 
                 5 
                 159399506 
                 ADRA1B 
               
               
                 cg03839709 
                 13 
                 96743492 
                 HS6ST3 
               
               
                 cg03867475 
                 21 
                 34444382 
                 OLIG1; OLIG1 
               
               
                 cg03884783 
                 19 
                 37957997 
                 ZNF569; ZNF569 
               
               
                 cg03921753 
                 16 
                 28074670 
                 GSG1L 
               
               
                 cg04075191 
                 2 
                 115919785 
                 DPP10; DPP10; DPP10 
               
               
                 cg04100696 
                 11 
                 12030268 
                 DKK3; DKK3; DKK3 
               
               
                 cg04105282 
                 10 
                 99790170 
                 CRTAC1 
               
               
                 cg04115680 
                 7 
                 75889229 
                 SRRM3 
               
               
                 cg04123776 
                 1 
                 170630602 
               
               
                 cg04172348 
                 3 
                 12046004 
                 SYN2; SYN2; SYN2; SYN2 
               
               
                 cg04182321 
                 11 
                 107799979 
                 RAB39 
               
               
                 cg04184836 
                 15 
                 83316640 
                 CPEB1; CPEB1 
               
               
                 cg04222358 
                 3 
                 2140256 
               
               
                 cg04347874 
                 14 
                 36987408 
                 NKX2-1; NKX2-1 
               
               
                 cg04425632 
                 7 
                 137531612 
                 DGKI 
               
               
                 cg04557544 
                 16 
                 12996046 
                 SHISA9; SHISA9 
               
               
                 cg04578774 
                 11 
                 44332664 
                 ALX4 
               
               
                 cg04578997 
                 12 
                 104850759 
                 CHST11 
               
               
                 cg04585612 
                 16 
                 88449996 
               
               
                 cg04719903 
                 1 
                 1181956 
                 FAM132A 
               
               
                 cg04737916 
                 12 
                 133196028 
                 P2RX2; P2RX2; P2RX2; P2RX2; P2RX2; P2RX2 
               
               
                 cg04741853 
                 3 
                 44037189 
               
               
                 cg04784475 
                 19 
                 38183130 
                 ZNF781; ZNF781 
               
               
                 cg04804618 
                 10 
                 131761386 
                 EBF3 
               
               
                 cg04819760 
                 10 
                 22765645 
               
               
                 cg04865110 
                 4 
                 6202558 
                 JAKMIP1; JAKMIP1 
               
               
                 cg04867733 
                 1 
                 77747987 
                 AK5; AK5; AK5 
               
               
                 cg04907523 
                 1 
                 213124896 
                 VASH2; VASH2; VASH2 
               
               
                 cg04912999 
                 3 
                 142682652 
                 PAQR9 
               
               
                 cg04922681 
                 13 
                 43149234 
                 TNFSF11; TNFSF11 
               
               
                 cg04981611 
                 2 
                 47798477 
                 KCNK12 
               
               
                 cg05033271 
                 8 
                 89340069 
                 MMP16; MMP16 
               
               
                 cg05119480 
                 12 
                 104850745 
                 CHST11 
               
               
                 cg05135549 
                 22 
                 17850690 
               
               
                 cg05142211 
                 3 
                 181430485 
                 SOX2OT; SOX2 
               
               
                 cg05143123 
                 5 
                 136834877 
                 SPOCK1; SPOCK1 
               
               
                 cg05191076 
                 4 
                 66536186 
                 EPHA5; EPHA5 
               
               
                 cg05218346 
                 14 
                 70041283 
               
               
                 cg05237641 
                 10 
                 128077307 
                 ADAM12; ADAM12 
               
               
                 cg05239311 
                 15 
                 78913147 
                 CHRNA3; CHRNA3; CHRNA3; CHRNA3 
               
               
                 cg05249988 
                 19 
                 58951684 
                 ZNF132 
               
               
                 cg05251676 
                 5 
                 38258884 
                 EGFLAM 
               
               
                 cg05258261 
                 3 
                 140770608 
                 SPSB4 
               
               
                 cg05293775 
                 8 
                 33457483 
                 DUSP26 
               
               
                 cg05336115 
                 20 
                 983104 
                 RSPO4; RSPO4 
               
               
                 cg05347845 
                 1 
                 229569892 
                 ACTA1 
               
               
                 cg05352500 
                 19 
                 34972277 
                 WTIP 
               
               
                 cg05377226 
                 1 
                 171810910 
                 DNM3; DNM3 
               
               
                 cg05446010 
                 6 
                 11044558 
                 ELOVL2; ELOVL2 
               
               
                 cg05470643 
                 7 
                 155579830 
               
               
                 cg05505803 
                 13 
                 96296997 
                 DZIP1; DZIP1 
               
               
                 cg05522774 
                 21 
                 34443443 
                 OLIG1; OLIG1 
               
               
                 cg05648010 
                 5 
                 53545 
               
               
                 cg05655837 
                 6 
                 166582188 
                 T 
               
               
                 cg05660179 
                 2 
                 170218690 
                 LRP2 
               
               
                 cg05802452 
                 1 
                 228194476 
                 WNT3A 
               
               
                 cg05804863 
                 15 
                 79724519 
                 KIAA1024 
               
               
                 cg05829782 
                 14 
                 74707911 
                 VSX2 
               
               
                 cg05841659 
                 7 
                 64712472 
               
               
                 cg05849857 
                 13 
                 39261425 
                 FREM2; FREM2 
               
               
                 cg05874561 
                 4 
                 154709828 
                 SFRP2 
               
               
                 cg05916744 
                 11 
                 119292737 
                 THY1 
               
               
                 cg05924652 
                 6 
                 39016363 
                 GLP1R 
               
               
                 cg05930881 
                 8 
                 11560540 
                 GATA4 
               
               
                 cg05950570 
                 7 
                 132261418 
                 PLXNA4; PLXNA4; PLXNA4 
               
               
                 cg06048524 
                 10 
                 44880542 
                 CXCL12; CXCL12; CXCL12 
               
               
                 cg06073449 
                 6 
                 166582310 
                 T 
               
               
                 cg06094615 
                 10 
                 50887578 
                 C10orf53; C10orf53 
               
               
                 cg06122148 
                 11 
                 98891553 
                 CNTN5; CNTN5 
               
               
                 cg06122635 
                 2 
                 105461368 
               
               
                 cg06178563 
                 20 
                 21494712 
                 NKX2-2 
               
               
                 cg06211893 
                 1 
                 171810778 
                 DNM3; DNM3; DNM3; DNM3 
               
               
                 cg06215569 
                 1 
                 110611465 
                 ALX3 
               
               
                 cg06241792 
                 12 
                 21680669 
                 C12orf39 
               
               
                 cg06274396 
                 4 
                 185941625 
                 HELT 
               
               
                 cg06279276 
                 16 
                 67184164 
                 B3GNT9 
               
               
                 cg06319822 
                 16 
                 215960 
                 HBM 
               
               
                 cg06399148 
                 8 
                 104153148 
                 BAALC; BAALC; C8orf56 
               
               
                 cg06401021 
                 6 
                 55443868 
                 HMGCLL1; HMGCLL1; HMGCLL1; HMGCLL1 
               
               
                 cg06445348 
                 1 
                 166917009 
                 ILDR2 
               
               
                 cg06481168 
                 4 
                 165878055 
                 C4orf39; TRIM61 
               
               
                 cg06525651 
                 10 
                 128994297 
                 FAM196A; FAM196A; DOCK1 
               
               
                 cg06554120 
                 5 
                 11385067 
                 CTNND2 
               
               
                 cg06558014 
                 6 
                 100051116 
               
               
                 cg06560887 
                 11 
                 33890371 
                 LMO2; LMO2; LMO2 
               
               
                 cg06570025 
                 21 
                 34444245 
                 OLIG1; OLIG1 
               
               
                 cg06570167 
                 7 
                 108095719 
                 NRCAM; NRCAM 
               
               
                 cg06573787 
                 8 
                 143070187 
               
               
                 cg06577045 
                 6 
                 105628022 
                 POPDC3 
               
               
                 cg06598091 
                 12 
                 11653600 
               
               
                 cg06598836 
                 3 
                 2140699 
               
               
                 cg06648277 
                 10 
                 134600489 
                 NKX6-2 
               
               
                 cg06651311 
                 4 
                 37246230 
                 KIAA1239 
               
               
                 cg06664085 
                 10 
                 28287942 
                 ARMC4; ARMC4 
               
               
                 cg06668300 
                 2 
                 95691755 
                 MAL; MAL; MAL; MAL 
               
               
                 cg06674731 
                 2 
                 154335014 
                 RPRM 
               
               
                 cg06695611 
                 2 
                 180726328 
                 ZNF385B; MIR1258 
               
               
                 cg06740629 
                 6 
                 94129627 
                 EPHA7 
               
               
                 cg06749715 
                 14 
                 37132291 
                 PAX9 
               
               
                 cg06759058 
                 6 
                 28602864 
               
               
                 cg06809252 
                 1 
                 110612044 
                 ALX3 
               
               
                 cg06862374 
                 2 
                 219736549 
                 WNT6 
               
               
                 cg06997381 
                 5 
                 6449090 
                 UBE2QL1 
               
               
                 cg07005523 
                 1 
                 107683187 
                 NTNG1; NTNG1; NTNG1 
               
               
                 cg07014673 
                 2 
                 237078733 
               
               
                 cg07017374 
                 13 
                 28674451 
                 FLT3 
               
               
                 cg07028533 
                 7 
                 145813439 
                 CNTNAP2 
               
               
                 cg07028821 
                 7 
                 140773905 
               
               
                 cg07057177 
                 7 
                 132261393 
                 PLXNA4; PLXNA4; PLXNA4 
               
               
                 cg07068327 
                 10 
                 134901279 
                 GPR123 
               
               
                 cg07104660 
                 8 
                 67873511 
               
               
                 cg07139509 
                 14 
                 70038717 
                 C14orf162 
               
               
                 cg07155336 
                 1 
                 107683775 
                 NTNG1; NTNG1; NTNG1 
               
               
                 cg07161721 
                 8 
                 72459953 
               
               
                 cg07162571 
                 8 
                 41624841 
                 ANK1; ANK1; ANK1; ANK1; ANK1 
               
               
                 cg07167168 
                 20 
                 41818788 
                 PTPRT; PTPRT 
               
               
                 cg07195011 
                 5 
                 11904114 
                 CTNND2 
               
               
                 cg07254054 
                 3 
                 96533258 
                 EPHA6 
               
               
                 cg07258916 
                 7 
                 132262353 
                 PLXNA4; PLXNA4; PLXNA4 
               
               
                 cg07283114 
                 8 
                 65489065 
                 LOC401463 
               
               
                 cg07295964 
                 5 
                 175223982 
                 CPLX2 
               
               
                 cg07319626 
                 2 
                 207308244 
                 ADAM23 
               
               
                 cg07360792 
                 5 
                 122425702 
                 PRDM6 
               
               
                 cg07399369 
                 3 
                 142838082 
                 CHST2 
               
               
                 cg07413609 
                 7 
                 42276816 
                 GLI3 
               
               
                 cg07434402 
                 11 
                 84431535 
                 DLG2; DLG2 
               
               
                 cg07451080 
                 3 
                 44041025 
               
               
                 cg07548607 
                 2 
                 187713964 
                 ZSWIM2 
               
               
                 cg07663789 
                 5 
                 32711429 
                 NPR3 
               
               
                 cg07680167 
                 11 
                 17717574 
               
               
                 cg07690181 
                 5 
                 83679643 
                 EDIL3 
               
               
                 cg07780095 
                 12 
                 85874296 
                 ALX1 
               
               
                 cg07785314 
                 20 
                 61885285 
                 FLJ16779; NKAIN4 
               
               
                 cg07785447 
                 14 
                 95235127 
                 GSC 
               
               
                 cg07821427 
                 16 
                 77822419 
                 VAT1L 
               
               
                 cg07832473 
                 5 
                 33936253 
                 RXFP3 
               
               
                 cg07842403 
                 3 
                 134515143 
                 EPHB1 
               
               
                 cg07850527 
                 16 
                 89268040 
               
               
                 cg07922007 
                 8 
                 67874858 
               
               
                 cg07931391 
                 13 
                 100608263 
               
               
                 cg07969676 
                 8 
                 10590641 
               
               
                 cg07976064 
                 11 
                 120435056 
               
               
                 cg07994622 
                 20 
                 4804052 
                 RASSF2 
               
               
                 cg08001895 
                 6 
                 94129582 
                 EPHA7 
               
               
                 cg08056146 
                 8 
                 10588013 
                 SOX7; SOX7 
               
               
                 cg08079580 
                 10 
                 133795885 
                 BNIP3 
               
               
                 cg08117309 
                 14 
                 33403862 
               
               
                 cg08132931 
                 2 
                 70994962 
                 ADD2; ADD2; ADD2; ADD2; ADD2 
               
               
                 cg08145590 
                 3 
                 119422161 
                 C3orf15 
               
               
                 cg08154348 
                 6 
                 84562930 
                 RIPPLY2 
               
               
                 cg08157228 
                 16 
                 86544308 
                 FOXF1 
               
               
                 cg08185661 
                 11 
                 7273498 
                 SYT9 
               
               
                 cg08213098 
                 1 
                 35395837 
               
               
                 cg08261094 
                 7 
                 37956276 
                 SFRP4; SFRP4 
               
               
                 cg08265644 
                 14 
                 70655871 
                 SLC8A3; SLC8A3; SLC8A3; SLC8A3 
               
               
                 cg08283882 
                 8 
                 25901017 
                 EBF2 
               
               
                 cg08315770 
                 6 
                 39281885 
                 KCNK17; KCNK17 
               
               
                 cg08322034 
                 6 
                 80657412 
                 ELOVL4 
               
               
                 cg08372619 
                 8 
                 109799518 
                 TMEM74 
               
               
                 cg08377398 
                 4 
                 6202553 
                 JAKMIP1; JAKMIP1 
               
               
                 cg08384637 
                 16 
                 86601133 
                 FOXC2 
               
               
                 cg08394412 
                 16 
                 50875140 
               
               
                 cg08402652 
                 11 
                 94501461 
                 AMOTL1 
               
               
                 cg08408994 
                 11 
                 44330958 
                 ALX4 
               
               
                 cg08413157 
                 20 
                 41818756 
                 PTPRT; PTPRT 
               
               
                 cg08448701 
                 20 
                 21686282 
                 PAX1 
               
               
                 cg08453926 
                 13 
                 27131683 
                 WASF3 
               
               
                 cg08458292 
                 1 
                 57890610 
                 DAB1 
               
               
                 cg08491964 
                 18 
                 53255771 
                 TCF4; TCF4; TCF4; TCF4 
               
               
                 cg08507422 
                 7 
                 1272512 
                 UNCX 
               
               
                 cg08521987 
                 10 
                 119000927 
                 SLC18A2 
               
               
                 cg08568720 
                 20 
                 61051432 
                 GATA5 
               
               
                 cg08606911 
                 1 
                 165325231 
                 LMX1A 
               
               
                 cg08620044 
                 5 
                 87980976 
                 LOC645323 
               
               
                 cg08632164 
                 7 
                 65971372 
               
               
                 cg08663159 
                 4 
                 101111872 
                 DDIT4L 
               
               
                 cg08675193 
                 3 
                 186080245 
                 DGKG; DGKG; DGKG 
               
               
                 cg08675717 
                 20 
                 58180241 
                 PHACTR3 
               
               
                 cg08696727 
                 10 
                 28034797 
                 MKX 
               
               
                 cg08705697 
                 13 
                 67804744 
                 PCDH9; PCDH9 
               
               
                 cg08750951 
                 4 
                 89378894 
                 HERC5 
               
               
                 cg08769966 
                 15 
                 92937735 
                 ST8SIA2 
               
               
                 cg08788717 
                 11 
                 8615506 
                 STK33 
               
               
                 cg08791131 
                 16 
                 58497801 
                 NDRG4; NDRG4; NDRG4 
               
               
                 cg08812555 
                 10 
                 54074788 
                 DKK1 
               
               
                 cg08848774 
                 17 
                 43047733 
               
               
                 cg08858437 
                 3 
                 142838938 
                 CHST2; CHST2 
               
               
                 cg08870743 
                 21 
                 34398199 
                 OLIG2 
               
               
                 cg08901662 
                 2 
                 131595321 
               
               
                 cg08912051 
                 6 
                 30227783 
                 HLA-L 
               
               
                 cg08921126 
                 20 
                 10199441 
                 SNAP25; SNAP25 
               
               
                 cg08933939 
                 6 
                 100061504 
                 PRDM13 
               
               
                 cg08969532 
                 10 
                 99790438 
                 CRTAC1; CRTAC1 
               
               
                 cg08992305 
                 4 
                 165878219 
                 TRIM61; C4orf39 
               
               
                 cg09053680 
                 10 
                 135044114 
                 UTF1 
               
               
                 cg09088988 
                 5 
                 146614298 
                 STK32A; STK32A 
               
               
                 cg09117206 
                 4 
                 109684077 
                 AGXT2L1; AGXT2L1; AGXT2L1; AGXT2L1; 
               
               
                   
                   
                   
                 AGXT2L1; AGXT2L1; AGXT2L1; AGXT2L1 
               
               
                 cg09125812 
                 8 
                 41625127 
                 ANK1; ANK1; ANK1; ANK1; ANK1 
               
               
                 cg09141953 
                 20 
                 62948235 
               
               
                 cg09150117 
                 7 
                 96653867 
                 DLX5 
               
               
                 cg09196068 
                 20 
                 61885270 
                 FLJ16779; NKAIN4 
               
               
                 cg09201151 
                 15 
                 84116151 
                 SH3GL3; SH3GL3; SH3GL3 
               
               
                 cg09225230 
                 1 
                 236558465 
                 EDARADD; EDARADD 
               
               
                 cg09251429 
                 11 
                 124735128 
                 ROBO3 
               
               
                 cg09279240 
                 2 
                 180726252 
                 ZNF385B; MIR1258 
               
               
                 cg09279949 
                 20 
                 23030250 
                 THBD; THBD 
               
               
                 cg09339194 
                 20 
                 61051585 
                 GATA5 
               
               
                 cg09339301 
                 6 
                 163836245 
                 QKI; QKI; QKI; QKI 
               
               
                 cg09360501 
                 19 
                 22018958 
                 ZNF43; ZNF43 
               
               
                 cg09365557 
                 17 
                 59477564 
                 TBX2 
               
               
                 cg09440289 
                 12 
                 15475990 
                 PTPRO; PTPRO 
               
               
                 cg09462445 
                 2 
                 217559131 
                 IGFBP5 
               
               
                 cg09493505 
                 7 
                 49813111 
                 VWC2 
               
               
                 cg09510559 
                 19 
                 36335144 
                 NPHS1 
               
               
                 cg09528825 
                 16 
                 28074388 
                 GSG1L 
               
               
                 cg09553380 
                 2 
                 207308829 
                 ADAM23 
               
               
                 cg09557387 
                 1 
                 207818395 
                 CR1L 
               
               
                 cg09571420 
                 7 
                 145813008 
                 CNTNAP2 
               
               
                 cg09638407 
                 3 
                 142839022 
                 CHST2; CHST2 
               
               
                 cg09639725 
                 10 
                 134901294 
                 GPR123 
               
               
                 cg09671258 
                 1 
                 180202530 
                 LHX4 
               
               
                 cg09671810 
                 11 
                 94501636 
                 AMOTL1; AMOTL1 
               
               
                 cg09684233 
                 2 
                 175206966 
               
               
                 cg09754845 
                 7 
                 1408818 
               
               
                 cg09767602 
                 4 
                 183370138 
                 ODZ3 
               
               
                 cg09768093 
                 1 
                 32930511 
                 ZBTB8B 
               
               
                 cg09772661 
                 19 
                 7794952 
                 CLEC4G 
               
               
                 cg09775312 
                 10 
                 93392839 
                 PPP1R3C; PPP1R3C 
               
               
                 cg09793584 
                 1 
                 156391310 
                 C1orf61; MIR9-1 
               
               
                 cg09831026 
                 12 
                 133485765 
               
               
                 cg09853371 
                 4 
                 57522145 
                 HOPX; HOPX; HOPX; HOPX; HOPX 
               
               
                 cg09873164 
                 1 
                 152488093 
                 CRCT1 
               
               
                 cg09880551 
                 21 
                 42218932 
                 DSCAM; DSCAM 
               
               
                 cg09935282 
                 10 
                 118897280 
                 VAX1; VAX1 
               
               
                 cg09949775 
                 19 
                 18902107 
                 COMP; COMP 
               
               
                 cg09979256 
                 6 
                 127440104 
                 RSPO3; RSPO3 
               
               
                 cg09987011 
                 20 
                 44936040 
               
               
                 cg09997760 
                 3 
                 179169556 
                 GNB4 
               
               
                 cg10042799 
                 14 
                 95236123 
                 GSC 
               
               
                 cg10111292 
                 12 
                 106975112 
               
               
                 cg10124413 
                 18 
                 73167919 
               
               
                 cg10158080 
                 12 
                 24715864 
                 SOX5 
               
               
                 cg10172415 
                 3 
                 71803558 
                 GPR27; EIF4E3; EIF4E3 
               
               
                 cg10229294 
                 12 
                 113903210 
                 LHX5 
               
               
                 cg10245915 
                 10 
                 119001478 
                 SLC18A2 
               
               
                 cg10249705 
                 11 
                 106890150 
                 GUCY1A2 
               
               
                 cg10273340 
                 16 
                 56224793 
                 GNAO1; GNAO1; LOC283856 
               
               
                 cg10292139 
                 8 
                 97507561 
                 SDC2 
               
               
                 cg10325478 
                 14 
                 88793021 
                 KCNK10; KCNK10 
               
               
                 cg10356613 
                 17 
                 35294491 
                 LHX1 
               
               
                 cg10362542 
                 17 
                 77179709 
                 HRNBP3 
               
               
                 cg10364513 
                 1 
                 165414379 
                 RXRG; RXRG; RXRG; RXRG 
               
               
                 cg10372047 
                 5 
                 63461930 
                 RNF180; RNF180 
               
               
                 cg10383019 
                 11 
                 8103101 
                 TUB; TUB 
               
               
                 cg10457056 
                 21 
                 44494997 
                 CBS 
               
               
                 cg10471437 
                 16 
                 28074462 
                 GSG1L 
               
               
                 cg10507508 
                 19 
                 30719828 
               
               
                 cg10512745 
                 1 
                 50884480 
                 DMRTA2 
               
               
                 cg10530851 
                 14 
                 37051417 
                 NKX2-8 
               
               
                 cg10626816 
                 1 
                 39025249 
               
               
                 cg10644072 
                 21 
                 42218551 
                 DSCAM 
               
               
                 cg10684547 
                 7 
                 155580133 
               
               
                 cg10716835 
                 10 
                 94834582 
                 CYP26A1; CYP26A1 
               
               
                 cg10732215 
                 10 
                 22625465 
               
               
                 cg10838789 
                 8 
                 67940989 
                 LRRC67 
               
               
                 cg10852177 
                 7 
                 84816454 
               
               
                 cg10864596 
                 5 
                 178487382 
                 ZNF354C 
               
               
                 cg10864878 
                 15 
                 47477004 
               
               
                 cg10886442 
                 3 
                 142838320 
                 CHST2 
               
               
                 cg10979880 
                 6 
                 105584689 
                 BVES; BVES 
               
               
                 cg11019211 
                 17 
                 56833043 
                 PPM1E 
               
               
                 cg11090352 
                 3 
                 96532043 
                 EPHA6 
               
               
                 cg11092616 
                 6 
                 72596493 
                 RIMS1 
               
               
                 cg11111132 
                 11 
                 8041137 
               
               
                 cg11113760 
                 2 
                 180726247 
                 ZNF385B; MIR125B 
               
               
                 cg11117364 
                 11 
                 94501718 
                 AMOTL1 
               
               
                 cg11198128 
                 11 
                 65601332 
                 SNX32 
               
               
                 cg11199770 
                 19 
                 31841663 
                 TSHZ3 
               
               
                 cg11200635 
                 10 
                 43573195 
                 RET; RET 
               
               
                 cg11229185 
                 10 
                 22625274 
               
               
                 cg11235498 
                 3 
                 140771656 
                 SPSB4 
               
               
                 cg11253514 
                 1 
                 228604240 
                 TRIM17; TRIM17; TRIM17; TRIM17; TRIM17; 
               
               
                   
                   
                   
                 TRIM17; TRIM17; TRIMI7 
               
               
                 cg11258089 
                 5 
                 59189791 
                 PDE4D; PDE4D 
               
               
                 cg11281641 
                 2 
                 171674855 
                 GAD1; GAD1 
               
               
                 cg11342452 
                 10 
                 134600463 
                 NKX6-2 
               
               
                 cg11361827 
                 17 
                 45867446 
               
               
                 cg11398452 
                 10 
                 118896755 
                 VAX1; VAX1 
               
               
                 cg11398511 
                 1 
                 215256635 
                 KCNK2; KCNK2; KCNK2; KCNK2; KCNK2 
               
               
                 cg11416384 
                 4 
                 37246827 
                 KIAA1239 
               
               
                 cg11419456 
                 19 
                 37157861 
                 ZNF461 
               
               
                 cg11514698 
                 7 
                 108095912 
                 NRCAM; NRCAM 
               
               
                 cg11583963 
                 19 
                 53193912 
                 ZNF83 
               
               
                 cg11599539 
                 8 
                 72459614 
               
               
                 cg11616651 
                 19 
                 2251837 
                 AMH 
               
               
                 cg11630554 
                 4 
                 165878136 
                 TRIM61; C4orf39; C4orf39 
               
               
                 cg11687406 
                 20 
                 10199434 
                 SNAP25; SNAP25 
               
               
                 cg11699435 
                 13 
                 95365673 
                 SOX21 
               
               
                 cg11724516 
                 9 
                 115653222 
                 SLC46A2 
               
               
                 cg11730458 
                 13 
                 67805065 
                 PCDH9; PCDH9 
               
               
                 cg11747771 
                 9 
                 6645468 
                 GLDC 
               
               
                 cg11806672 
                 13 
                 79176608 
                 POU4F1 
               
               
                 cg11821817 
                 15 
                 79724517 
                 KIAA1024 
               
               
                 cg11832210 
                 10 
                 91295346 
                 SLC16A12 
               
               
                 cg11854806 
                 10 
                 82116365 
                 DYDC2; DYDC1 
               
               
                 cg11855526 
                 11 
                 30607068 
                 MPPED2 
               
               
                 cg11880855 
                 10 
                 16562917 
                 C1QL3 
               
               
                 cg11912330 
                 1 
                 161228674 
                 PCP4L1; PCP4L1 
               
               
                 cg11980016 
                 3 
                 96532859 
                 EPHA6 
               
               
                 cg11982072 
                 20 
                 61051348 
                 GATA5 
               
               
                 cg12002303 
                 15 
                 68113478 
               
               
                 cg12004183 
                 7 
                 71217124 
               
               
                 cg12005098 
                 10 
                 91295338 
                 SLC16A12 
               
               
                 cg12035092 
                 2 
                 149633226 
                 KIF5C 
               
               
                 cg12040830 
                 11 
                 112833773 
                 NCAM1; NCAM1; NCAM1 
               
               
                 cg12041848 
                 20 
                 45523294 
                 EYA2; EYA2; EYA2; EYA2 
               
               
                 cg12042659 
                 19 
                 58951599 
                 ZNF132 
               
               
                 cg12109566 
                 6 
                 30227986 
                 HLA-L 
               
               
                 cg12147137 
                 13 
                 27132130 
                 WASF3 
               
               
                 cg12188986 
                 11 
                 93063886 
                 CCDC67; CCDC67 
               
               
                 cg12217936 
                 3 
                 150804058 
                 MED12L 
               
               
                 cg12221475 
                 6 
                 1390622 
                 FOXF2 
               
               
                 cg12248614 
                 19 
                 41018880 
                 SPTBN4 
               
               
                 cg12379948 
                 17 
                 44896424 
                 WNT3 
               
               
                 cg12392473 
                 20 
                 48099331 
                 KCNB1 
               
               
                 cg12405785 
                 1 
                 221053409 
                 HLX 
               
               
                 cg12473285 
                 17 
                 41832975 
                 SOST 
               
               
                 cg12497564 
                 3 
                 139258295 
                 RBP1; RBP1; RBP1 
               
               
                 cg12515638 
                 7 
                 37956018 
                 SFRP4 
               
               
                 cg12573849 
                 2 
                 105470711 
                 POU3F3 
               
               
                 cg12602374 
                 5 
                 38557162 
                 LIFR; LIFR 
               
               
                 cg12605662 
                 18 
                 56935199 
                 RAX 
               
               
                 cg12615137 
                 3 
                 87040286 
                 VGLL3 
               
               
                 cg12623648 
                 5 
                 178487384 
                 ZNF354C 
               
               
                 cg12646649 
                 10 
                 102987257 
                 LBX1 
               
               
                 cg12658947 
                 11 
                 132952915 
                 OPCML 
               
               
                 cg12664209 
                 20 
                 13200954 
                 ISM1 
               
               
                 cg12686317 
                 15 
                 55880894 
                 PYGO1 
               
               
                 cg12740527 
                 11 
                 8289974 
               
               
                 cg12758636 
                 10 
                 31609882 
                 ZEB1; ZEB1; ZEB1; ZEB1; ZEB1 
               
               
                 cg12824796 
                 10 
                 131768928 
               
               
                 cg12859211 
                 11 
                 124735105 
                 ROBO3 
               
               
                 cg12861945 
                 4 
                 165878085 
                 C4orf39; TRIM61 
               
               
                 cg12865552 
                 17 
                 77721631 
               
               
                 cg12874092 
                 10 
                 17271519 
                 VIM 
               
               
                 cg12949975 
                 2 
                 20867352 
                 GDF7 
               
               
                 cg12975230 
                 18 
                 73167671 
               
               
                 cg12993163 
                 3 
                 157821407 
                 SHOX2; SHOX2; SHOX2 
               
               
                 cg13012916 
                 14 
                 36973691 
                 SFTA3 
               
               
                 cg13031432 
                 16 
                 58497767 
                 NDRG4; NDRG4; NDRG4 
               
               
                 cg13042543 
                 20 
                 30640256 
                 HCK 
               
               
                 cg13056495 
                 7 
                 134143249 
                 AKR1B1 
               
               
                 cg13186327 
                 12 
                 45444895 
                 DBX2 
               
               
                 cg13198321 
                 15 
                 58357891 
                 ALDH1A2; ALDH1A2; ALDH1A2; ALDH1A2 
               
               
                 cg13267264 
                 8 
                 70983600 
                 PRDM14 
               
               
                 cg13267931 
                 7 
                 101006308 
                 EMID2; EMID2 
               
               
                 cg13323701 
                 6 
                 118228508 
                 SLC35F1 
               
               
                 cg13334650 
                 11 
                 6440065 
                 APBB1; APBB1 
               
               
                 cg13346411 
                 11 
                 6280512 
                 CCKBR 
               
               
                 cg13348059 
                 3 
                 44727069 
               
               
                 cg13349651 
                 5 
                 33936307 
                 RXFP3 
               
               
                 cg13357482 
                 6 
                 105628017 
                 POPDC3 
               
               
                 cg13365524 
                 6 
                 100902093 
                 SIM1 
               
               
                 cg13390630 
                 20 
                 44803246 
                 CDH22 
               
               
                 cg13405332 
                 17 
                 19483367 
               
               
                 cg13441730 
                 9 
                 10613328 
                 PTPRD; PTPRD 
               
               
                 cg13457172 
                 10 
                 118897847 
                 VAX1; VAX1 
               
               
                 cg13459498 
                 20 
                 42544792 
                 TOX2; TOX2; TOX2; TOX2; TOX2 
               
               
                 cg13464448 
                 11 
                 130297513 
                 ADAMTS8 
               
               
                 cg13482432 
                 9 
                 79633350 
                 FOXB2 
               
               
                 cg13561592 
                 9 
                 118916976 
                 PAPPA 
               
               
                 cg13562542 
                 3 
                 71803339 
                 GPR27; EIF4E3; EIF4E3 
               
               
                 cg13564825 
                 19 
                 38747201 
                 PPP1R14A 
               
               
                 cg13571707 
                 15 
                 79383980 
                 RASGRF1; RASGRF1 
               
               
                 cg13603508 
                 12 
                 39299326 
                 CPNE8 
               
               
                 cg13606569 
                 9 
                 113341525 
                 SVEP1 
               
               
                 cg13632816 
                 9 
                 113341925 
                 SVEP1; SVEP1 
               
               
                 cg13689003 
                 1 
                 156406102 
               
               
                 cg13703576 
                 11 
                 69632335 
                 FGF3 
               
               
                 cg13725782 
                 6 
                 105584718 
                 BVES; BVES 
               
               
                 cg13742526 
                 19 
                 2252432 
                 JSRP1 
               
               
                 cg13756879 
                 11 
                 2161473 
                 INS-IGF2; IGF2AS; IGF2; IGF2; IGF2AS; IGF2 
               
               
                 cg13758646 
                 9 
                 101469711 
                 GABBR2 
               
               
                 cg13758712 
                 21 
                 28218959 
                 ADAMTS1 
               
               
                 cg13768269 
                 9 
                 114140 
               
               
                 cg13776340 
                 6 
                 80656888 
                 ELOVL4 
               
               
                 cg13798146 
                 15 
                 83875703 
                 HDGFRP3 
               
               
                 cg13845982 
                 20 
                 61051029 
                 GATA5 
               
               
                 cg13913015 
                 2 
                 47797963 
                 KCNK12 
               
               
                 cg13916740 
                 19 
                 56904997 
                 ZNF582 
               
               
                 cg13928709 
                 5 
                 176237221 
                 UNC5A 
               
               
                 cg13958426 
                 1 
                 169396637 
                 C1orf114; C1orf114 
               
               
                 cg13969001 
                 1 
                 18958084 
                 PAX7; PAX7; PAX7; PAX7; PAX7; PAX7 
               
               
                 cg14019323 
                 12 
                 65218413 
               
               
                 cg14044640 
                 7 
                 27187560 
                 HOXA6 
               
               
                 cg14045872 
                 7 
                 49813065 
                 VWC2 
               
               
                 cg14060111 
                 20 
                 13200944 
                 ISM1 
               
               
                 cg14081924 
                 3 
                 142682378 
                 PAQR9 
               
               
                 cg14101302 
                 6 
                 72596557 
                 RIMS1 
               
               
                 cg14123923 
                 13 
                 79176572 
                 POU4F1 
               
               
                 cg14159026 
                 6 
                 105584551 
                 BVES; BVES 
               
               
                 cg14168923 
                 13 
                 28366606 
                 GSX1 
               
               
                 cg14174099 
                 14 
                 70655862 
                 SLC8A3; SLC8A3; SLC8A3; SLC8A3 
               
               
                 cg14189141 
                 9 
                 1042605 
               
               
                 cg14242042 
                 12 
                 24715250 
                 SOX5 
               
               
                 cg14267725 
                 2 
                 100721038 
                 AFF3; AFF3 
               
               
                 cg14314653 
                 6 
                 105584709 
                 BVES; BVES 
               
               
                 cg14352983 
                 18 
                 6414976 
                 L3MBTL4 
               
               
                 cg14364356 
                 21 
                 44495495 
                 CBS 
               
               
                 cg14380270 
                 17 
                 33700747 
                 SLFN11; SLFN11; SLFN11; SLFN11; SLFN11 
               
               
                 cg14409023 
                 14 
                 57283436 
                 OTX2OS1 
               
               
                 cg14414971 
                 7 
                 3340979 
                 SDK1 
               
               
                 cg14421860 
                 1 
                 101004934 
                 GPR88 
               
               
                 cg14487131 
                 9 
                 79633737 
                 FOXB2 
               
               
                 cg14556070 
                 19 
                 58458917 
                 ZNF256; ZNF256 
               
               
                 cg14568217 
                 5 
                 176057061 
                 SNCB; EIF4E1B; SNCB 
               
               
                 cg14591786 
                 5 
                 63461574 
                 RNF180; RNF180 
               
               
                 cg14649650 
                 10 
                 13933996 
                 FRMD4A 
               
               
                 cg14657517 
                 11 
                 32456910 
                 WT1; WIT1; WT1; WT1; WT1; WT1; WT1; WT1; WT1 
               
               
                 cg14660839 
                 13 
                 28674720 
                 FLT3; FLT3 
               
               
                 cg14667871 
                 5 
                 15500833 
                 FBXL7 
               
               
                 cg14730085 
                 19 
                 39522548 
                 FBXO27 
               
               
                 cg14730445 
                 12 
                 101603581 
                 SLC5A8 
               
               
                 cg14732324 
                 5 
                 528621 
               
               
                 cg14839351 
                 18 
                 35146227 
                 BRUNOL4; BRUNOL4; BRUNOL4; BRUNOL4 
               
               
                 cg14843800 
                 12 
                 119419786 
                 SRRM4 
               
               
                 cg14866595 
                 4 
                 4873442 
               
               
                 cg14896516 
                 7 
                 30722361 
                 CRHR2 
               
               
                 cg14900471 
                 8 
                 11561620 
                 GATA4 
               
               
                 cg14921743 
                 20 
                 44650449 
                 SLC12A5 
               
               
                 cg15007959 
                 19 
                 50931432 
                 SPIB 
               
               
                 cg15041550 
                 6 
                 39016590 
                 GLP1R; GLP1R 
               
               
                 cg15131808 
                 5 
                 528580 
               
               
                 cg15139588 
                 19 
                 37997867 
                 ZNF793; ZNF793 
               
               
                 cg15146859 
                 18 
                 74961737 
                 GALR1 
               
               
                 cg15212349 
                 5 
                 1444852 
                 SLC6A3 
               
               
                 cg15221604 
                 11 
                 124738735 
                 ROBO3 
               
               
                 cg15244223 
                 6 
                 118228493 
                 SLC35F1 
               
               
                 cg15267232 
                 10 
                 8097689 
                 GATA3; GATA3 
               
               
                 cg15344220 
                 11 
                 8040551 
               
               
                 cg15376615 
                 5 
                 153858822 
                 HAND1 
               
               
                 cg15409931 
                 19 
                 34973341 
                 WTIP 
               
               
                 cg15431821 
                 15 
                 79724788 
                 KIAA1024 
               
               
                 cg15449956 
                 8 
                 106331995 
                 ZFPM2 
               
               
                 cg15553598 
                 5 
                 175792973 
                 ARL10 
               
               
                 cg15562912 
                 3 
                 140770617 
                 SPSB4 
               
               
                 cg15571277 
                 20 
                 61885249 
                 FLJ16779; NKAIN4 
               
               
                 cg15573040 
                 15 
                 92938295 
                 ST8SIA2 
               
               
                 cg15576900 
                 1 
                 44883697 
                 RNF220 
               
               
                 cg15607538 
                 12 
                 133484853 
               
               
                 cg15613567 
                 10 
                 134901497 
                 GPR123; GPR123 
               
               
                 cg15645638 
                 8 
                 109799603 
                 TMEM74 
               
               
                 cg15654121 
                 1 
                 34630944 
                 CSMD2 
               
               
                 cg15674193 
                 2 
                 238535910 
                 LRRFIP1 
               
               
                 cg15684724 
                 8 
                 67875033 
               
               
                 cg15707833 
                 8 
                 131455276 
               
               
                 cg15724184 
                 14 
                 70346477 
                 SMOC1; SMOC1 
               
               
                 cg15744359 
                 8 
                 67940823 
                 LRRC67 
               
               
                 cg15760257 
                 17 
                 26699169 
                 SARM1 
               
               
                 cg15775138 
                 7 
                 127744389 
               
               
                 cg15778437 
                 11 
                 31839521 
                 PAX6 
               
               
                 cg15792338 
                 19 
                 31840743 
                 TSHZ3 
               
               
                 cg15825786 
                 10 
                 134901297 
                 GPR123 
               
               
                 cg15863924 
                 20 
                 3388269 
                 C20orf194 
               
               
                 cg15898840 
                 7 
                 45960834 
                 IGFBP3; IGFBP3; IGFBP3; IGFBP3 
               
               
                 cg15919396 
                 7 
                 108097187 
                 NRCAM; NRCAM 
               
               
                 cg15936446 
                 5 
                 42952369 
               
               
                 cg15971888 
                 8 
                 67089599 
                 CRH 
               
               
                 cg15987885 
                 1 
                 183386054 
                 NMNAT2 
               
               
                 cg15992284 
                 1 
                 91191254 
               
               
                 cg15992535 
                 5 
                 139228150 
                 NRG2; NRG2; NRG2; NRG2 
               
               
                 cg15994026 
                 4 
                 15780306 
                 CD38 
               
               
                 cg16015276 
                 8 
                 11550445 
               
               
                 cg16019809 
                 10 
                 126138593 
                 NKX1-2 
               
               
                 cg16041660 
                 12 
                 42983360 
                 PRICKLE1; PRICKLE1 
               
               
                 cg16043357 
                 10 
                 118897904 
                 VAX1; VAX1 
               
               
                 cg16172814 
                 10 
                 50969997 
                 OGDHL; OGDHL; OGDHL 
               
               
                 cg16250461 
                 6 
                 30227360 
                 HLA-L 
               
               
                 cg16276063 
                 3 
                 181421703 
                 SOX2OT 
               
               
                 cg16278512 
                 7 
                 12443529 
                 VWDE; VWDE 
               
               
                 cg16325777 
                 10 
                 43250569 
               
               
                 cg16332610 
                 15 
                 74658547 
                 CYP11A1; CYP11A1; CYP11A1 
               
               
                 cg16400999 
                 2 
                 180726349 
                 ZNF385B; MIR1258 
               
               
                 cg16419629 
                 3 
                 173115536 
                 NLGN1 
               
               
                 cg16423505 
                 13 
                 92051400 
                 GPC5 
               
               
                 cg16468187 
                 16 
                 4588687 
                 C16orf5 
               
               
                 cg16476975 
                 7 
                 155164995 
               
               
                 cg16477091 
                 17 
                 56833000 
                 PPM1E 
               
               
                 cg16478774 
                 6 
                 132722315 
                 MOXD1 
               
               
                 cg16480938 
                 18 
                 5895225 
               
               
                 cg16482474 
                 7 
                 151107637 
                 WDR86 
               
               
                 cg16485558 
                 5 
                 63461566 
                 RNF180; RNF180 
               
               
                 cg16499656 
                 7 
                 50344471 
                 IKZF1; IKZF1 
               
               
                 cg16501308 
                 18 
                 30350221 
                 KLHL14 
               
               
                 cg16528511 
                 6 
                 84562892 
                 RIPPLY2 
               
               
                 cg16556906 
                 6 
                 71666682 
                 B3GAT2; B3GAT2 
               
               
                 cg16557944 
                 1 
                 53068197 
                 GPX7 
               
               
                 cg16638385 
                 17 
                 41832753 
                 SOST 
               
               
                 cg16647921 
                 4 
                 41867533 
               
               
                 cg16697214 
                 7 
                 50343361 
                 IKZF1 
               
               
                 cg16712637 
                 12 
                 103352000 
                 ASCL1; ASCL1 
               
               
                 cg16714055 
                 20 
                 61051341 
                 GATA5 
               
               
                 cg16818740 
                 20 
                 4803300 
                 RASSF2 
               
               
                 cg16842053 
                 7 
                 3083333 
                 CARD11; CARD11 
               
               
                 cg16882226 
                 2 
                 101034257 
                 CHST10 
               
               
                 cg16910830 
                 7 
                 145813437 
                 CNTNAP2 
               
               
                 cg16915821 
                 11 
                 12030187 
                 DKK3; DKK3; DKK3 
               
               
                 cg16918905 
                 2 
                 220361609 
               
               
                 cg16935295 
                 8 
                 97506251 
                 SDC2; SDC2 
               
               
                 cg16949120 
                 10 
                 134599783 
                 NKX6-2 
               
               
                 cg16958716 
                 17 
                 56833425 
                 PPM1E 
               
               
                 cg16969623 
                 19 
                 54024182 
                 ZNF331; ZNF331 
               
               
                 cg17003293 
                 14 
                 36003826 
                 INSM2 
               
               
                 cg17009433 
                 9 
                 6645686 
                 GLDC; GLDC 
               
               
                 cg17093995 
                 7 
                 49815502 
                 VWC2 
               
               
                 cg17188046 
                 6 
                 166582197 
                 T 
               
               
                 cg17213402 
                 2 
                 5813650 
               
               
                 cg17267805 
                 10 
                 44880545 
                 CXCL12; CXCL12; CXCL12 
               
               
                 cg17276590 
                 10 
                 119304487 
                 EMX2OS; EMX2; EMX2 
               
               
                 cg17307479 
                 8 
                 65494101 
                 BHLHE22 
               
               
                 cg17309441 
                 8 
                 48100186 
               
               
                 cg17315500 
                 12 
                 103359572 
               
               
                 cg17344755 
                 3 
                 154797563 
                 MME; MME; MME; MME 
               
               
                 cg17349389 
                 2 
                 80530770 
                 CTNNA2; LRRTM1; CTNNA2 
               
               
                 cg17357285 
                 6 
                 28602938 
               
               
                 cg17361203 
                 11 
                 117666889 
                 DSCAML1 
               
               
                 cg17370163 
                 5 
                 63461654 
                 RNF180; RNF180 
               
               
                 cg17418463 
                 1 
                 35395541 
               
               
                 cg17429382 
                 19 
                 3786246 
                 MATK; MATK; MATK; MATK; MATK 
               
               
                 cg17464383 
                 5 
                 122426096 
                 PRDM6 
               
               
                 cg17470837 
                 4 
                 6201430 
                 JAKMIP1; JAKMIP1 
               
               
                 cg17498296 
                 10 
                 124907540 
                 HMX2 
               
               
                 cg17512353 
                 6 
                 30227802 
                 HLA-L 
               
               
                 cg17535595 
                 13 
                 53422808 
                 PCDH8; PCDH8 
               
               
                 cg17565078 
                 13 
                 27334723 
                 GPR12; GPR12 
               
               
                 cg17567560 
                 10 
                 105036863 
                 INA 
               
               
                 cg17627617 
                 3 
                 142682682 
                 PAQR9 
               
               
                 cg17688525 
                 18 
                 6414978 
                 L3MBTL4 
               
               
                 cg17714276 
                 4 
                 156588619 
                 GUCY1A3; GUCY1A3; GUCY1A3; GUCY1A3; 
               
               
                   
                   
                   
                 GUCY1A3; GUCY1A3; GUCY1A3 
               
               
                 cg17721710 
                 1 
                 220101698 
                 SLC30A10 
               
               
                 cg17757602 
                 5 
                 42952113 
               
               
                 cg17815538 
                 2 
                 238536315 
                 LRRFIP1 
               
               
                 cg17839237 
                 7 
                 19157193 
                 TWIST1; TWIST1 
               
               
                 cg17859110 
                 20 
                 41818770 
                 PTPRT; PTPRT 
               
               
                 cg17868340 
                 10 
                 125853676 
               
               
                 cg17898329 
                 4 
                 154713496 
               
               
                 cg17994139 
                 7 
                 27187556 
                 HOXA6 
               
               
                 cg17996619 
                 10 
                 134600701 
                 NKX6-2 
               
               
                 cg18013519 
                 4 
                 6473964 
                 PPP2R2C; PPP2R2C 
               
               
                 cg18035229 
                 8 
                 70984270 
                 PRDM14 
               
               
                 cg18066271 
                 5 
                 100236783 
                 ST8SIA4; ST8SIA4 
               
               
                 cg18120376 
                 4 
                 142054254 
                 RNF150; RNF150 
               
               
                 cg18174928 
                 5 
                 38557085 
                 LIFR; LIFR 
               
               
                 cg18180569 
                 1 
                 44883362 
                 RNF220 
               
               
                 cg18206027 
                 7 
                 49813486 
                 VWC2; VWC2 
               
               
                 cg18249634 
                 3 
                 32860467 
                 TRIM71 
               
               
                 cg18276638 
                 1 
                 214360619 
               
               
                 cg18278265 
                 20 
                 61051438 
                 GATA5 
               
               
                 cg18290848 
                 7 
                 89950671 
               
               
                 cg18313899 
                 6 
                 118228498 
                 SLC35F1 
               
               
                 cg18314424 
                 4 
                 184718605 
               
               
                 cg18326657 
                 6 
                 30227729 
                 HLA-L 
               
               
                 cg18402615 
                 10 
                 124896659 
                 HMX3 
               
               
                 cg18412834 
                 20 
                 61885291 
                 FLJ16779; NKAIN4 
               
               
                 cg18420512 
                 7 
                 128828982 
                 SMO; SMO 
               
               
                 cg18428688 
                 19 
                 58609744 
                 ZSCAN18; ZSCAN18; ZSCAN18; ZSCAN18 
               
               
                 cg18488855 
                 14 
                 27066634 
                 NOVA1; NOVA1; NOVA1 
               
               
                 cg18552861 
                 2 
                 20865845 
                 GDF7 
               
               
                 cg18560328 
                 11 
                 7273148 
                 SYT9 
               
               
                 cg18603228 
                 3 
                 13590439 
                 FBLN2; FBLN2 
               
               
                 cg18607529 
                 7 
                 50343869 
                 IKZF1 
               
               
                 cg18623980 
                 2 
                 45240563 
               
               
                 cg18624900 
                 10 
                 91295643 
                 SLC16A12 
               
               
                 cg18646207 
                 10 
                 118897836 
                 VAX1; VAX1 
               
               
                 cg18657094 
                 3 
                 2140030 
               
               
                 cg18689958 
                 5 
                 33936232 
                 RXFP3 
               
               
                 cg18710929 
                 6 
                 118228078 
                 SLC35F1 
               
               
                 cg18723978 
                 7 
                 42276814 
                 GLI3 
               
               
                 cg18749015 
                 6 
                 45631363 
               
               
                 cg18781240 
                 13 
                 27131676 
                 WASF3 
               
               
                 cg18786873 
                 1 
                 110610899 
                 ALX3 
               
               
                 cg18794839 
                 1 
                 215256262 
                 KCNK2; KCNK2; KCNK2 
               
               
                 cg18800085 
                 1 
                 167599719 
                 RCSD1 
               
               
                 cg18881684 
                 1 
                 70033592 
               
               
                 cg18920423 
                 10 
                 23481389 
                 PTF1A 
               
               
                 cg18935813 
                 1 
                 111149153 
                 KCNA2 
               
               
                 cg18972849 
                 4 
                 134067789 
               
               
                 cg18991611 
                 8 
                 49468828 
               
               
                 cg18996590 
                 8 
                 30890583 
                 WRN; PURG; PURG; PURG 
               
               
                 cg19054524 
                 20 
                 21686273 
                 PAX1 
               
               
                 cg19068510 
                 13 
                 100642106 
               
               
                 cg19079194 
                 2 
                 213403321 
                 ERBB4; ERBB4; ERBB4; ERBB4 
               
               
                 cg19118812 
                 7 
                 37488438 
                 ELMO1; ELMO1 
               
               
                 cg19126300 
                 11 
                 32457162 
                 WT1; WIT1; WT1; WT1; WT1 
               
               
                 cg19186145 
                 2 
                 45169562 
                 SIX3 
               
               
                 cg19194098 
                 10 
                 28287983 
                 ARMC4 
               
               
                 cg19206040 
                 1 
                 37500441 
                 GRIK3 
               
               
                 cg19241327 
                 7 
                 157484559 
                 PTPRN2; PTPRN2; PTPRN2 
               
               
                 cg19266910 
                 11 
                 107462445 
                 ELMOD1; LOC643923; ELMOD1 
               
               
                 cg19320476 
                 11 
                 82443592 
                 FAM181B 
               
               
                 cg19355087 
                 10 
                 134600295 
                 NKX6-2 
               
               
                 cg19412467 
                 2 
                 107502679 
                 ST6GAL2; ST6GAL2; ST6GAL2 
               
               
                 cg19427610 
                 12 
                 65515031 
                 WIF1; WIF1 
               
               
                 cg19443257 
                 3 
                 140770549 
                 SPSB4 
               
               
                 cg19461621 
                 18 
                 500979 
                 COLEC12 
               
               
                 cg19485202 
                 19 
                 18902081 
                 COMP; COMP 
               
               
                 cg19509715 
                 3 
                 44037128 
               
               
                 cg19544662 
                 2 
                 88752056 
                 FOXI3 
               
               
                 cg19570244 
                 11 
                 32457158 
                 WT1; WIT1; WT1; WT1; WT1 
               
               
                 cg19584875 
                 14 
                 90528213 
                 KCNK13; KCNK13 
               
               
                 cg19589811 
                 11 
                 82443961 
                 FAM181B 
               
               
                 cg19594305 
                 19 
                 34112991 
                 CHST8; CHST8; CHST8; CHST8 
               
               
                 cg19618483 
                 5 
                 32711355 
                 NPR3 
               
               
                 cg19655456 
                 19 
                 37959961 
                 ZNF570 
               
               
                 cg19665362 
                 15 
                 83316838 
                 CPEB1 
               
               
                 cg19721867 
                 10 
                 119001066 
                 SLC18A2 
               
               
                 cg19734015 
                 7 
                 94284432 
                 SGCE; SGCE; PEG10; SGCE; PEG10 
               
               
                 cg19736503 
                 6 
                 84563604 
                 RIPPLY2 
               
               
                 cg19752627 
                 7 
                 98467380 
                 TMEM130; TMEM130; TMEM130 
               
               
                 cg19761848 
                 2 
                 237076815 
                 GBX2 
               
               
                 cg19831575 
                 11 
                 69590090 
                 FGF4; FGF4 
               
               
                 cg19850348 
                 15 
                 55880997 
                 PYGO1 
               
               
                 cg19935171 
                 2 
                 39893078 
                 TMEM178; TMEM178; TMEM178 
               
               
                 cg19950455 
                 21 
                 44495595 
                 CBS 
               
               
                 cg20012008 
                 7 
                 69062534 
                 AUTS2; AUTS2; AUTS2 
               
               
                 cg20014049 
                 10 
                 23481385 
                 PTF1A 
               
               
                 cg20052751 
                 3 
                 157155332 
                 VEPH1; VEPH1; PTX3; VEPH1 
               
               
                 cg20078466 
                 7 
                 50344331 
                 IKZF1 
               
               
                 cg20129213 
                 8 
                 104512317 
                 RIMS2 
               
               
                 cg20162381 
                 12 
                 3310097 
                 TSPAN9; TSPAN9 
               
               
                 cg20183619 
                 7 
                 155241490 
               
               
                 cg20193324 
                 13 
                 26626134 
                 SHISA2 
               
               
                 cg20213228 
                 20 
                 61810348 
               
               
                 cg20232102 
                 19 
                 38747174 
                 PPP1R14A 
               
               
                 cg20250080 
                 17 
                 66596999 
                 FAM20A; FAM20A 
               
               
                 cg20265733 
                 20 
                 61051032 
                 GATA5 
               
               
                 cg20298273 
                 1 
                 156897330 
                 C1orf92 
               
               
                 cg20311863 
                 1 
                 91184126 
                 BARHL2 
               
               
                 cg20318608 
                 1 
                 179712591 
                 FAM163A 
               
               
                 cg20339230 
                 15 
                 92937360 
                 ST8SIA2 
               
               
                 cg20340508 
                 21 
                 34442377 
                 OLIG1 
               
               
                 cg20347882 
                 7 
                 155166554 
               
               
                 cg20478129 
                 14 
                 27067372 
                 NOVA1; NOVA1; NOVA1 
               
               
                 cg20483857 
                 2 
                 107502677 
                 ST6GAL2; ST6GAL2; ST6GAL2 
               
               
                 cg20498414 
                 20 
                 43439400 
                 RIMS4 
               
               
                 cg20541723 
                 3 
                 85007894 
                 CADM2; CADM2 
               
               
                 cg20560075 
                 5 
                 146257484 
                 PPP2R2B; PPP2R2B; PPP2R2B; PPP2R2B; 
               
               
                   
                   
                   
                 PPP2R2B; PPP2R2B; PPP2R2B 
               
               
                 cg20648847 
                 11 
                 66326767 
                 ACTN3 
               
               
                 cg20649951 
                 10 
                 88126306 
                 GRID1 
               
               
                 cg20656261 
                 20 
                 4803864 
                 RASSF2 
               
               
                 cg20737185 
                 6 
                 110679566 
                 C6orf186 
               
               
                 cg20740029 
                 12 
                 101603835 
                 SLC5A8; SLC5A8 
               
               
                 cg20761860 
                 5 
                 131992114 
               
               
                 cg20771178 
                 11 
                 8615675 
                 STK33 
               
               
                 cg20788479 
                 3 
                 179169536 
                 GNB4 
               
               
                 cg20842253 
                 2 
                 27529788 
                 TRIM54; TRIM54 
               
               
                 cg20870512 
                 7 
                 1272515 
                 UNCX 
               
               
                 cg20893717 
                 7 
                 100318190 
                 EPO 
               
               
                 cg20930060 
                 6 
                 163835395 
                 QKI; QKI; QKI; QKI 
               
               
                 cg20979852 
                 3 
                 140770683 
                 SPSB4 
               
               
                 cg20987924 
                 15 
                 60296981 
                 FOXB1 
               
               
                 cg21039708 
                 14 
                 57278729 
                 OTX2OS1 
               
               
                 cg21067341 
                 12 
                 96883381 
               
               
                 cg21068911 
                 11 
                 107462430 
                 ELMOD1; LOC643923; ELMOD1 
               
               
                 cg21121136 
                 3 
                 14852327 
               
               
                 cg21145136 
                 15 
                 84116115 
                 SH3GL3; SH3GL3; SH3GL3 
               
               
                 cg21173447 
                 21 
                 42218964 
                 DSCAM; DSCAM 
               
               
                 cg21189727 
                 8 
                 67940950 
                 LRRC67 
               
               
                 cg21240762 
                 8 
                 67089388 
                 CRH 
               
               
                 cg21258057 
                 20 
                 61885262 
                 FLJ16779; NKAIN4 
               
               
                 cg21338532 
                 2 
                 154335348 
                 RPRM 
               
               
                 cg21401219 
                 3 
                 150803669 
                 MED12L 
               
               
                 cg21401879 
                 2 
                 45162036 
               
               
                 cg21426003 
                 2 
                 237076811 
                 GBX2 
               
               
                 cg21521683 
                 12 
                 22487682 
                 ST8SIA1 
               
               
                 cg21548032 
                 12 
                 104850767 
                 CHST11 
               
               
                 cg21552709 
                 6 
                 94129636 
                 EPHA7 
               
               
                 cg21553524 
                 2 
                 39893185 
                 TMEM178; TMEM178 
               
               
                 cg21578219 
                 1 
                 18434542 
                 IGSF21; IGSF21 
               
               
                 cg21591173 
                 7 
                 69063475 
                 AUTS2; AUTS2; AUTS2 
               
               
                 cg21653184 
                 19 
                 58609361 
                 ZSCAN18; ZSCAN18; ZSCAN18, ZSCAN18; ZSCAN18 
               
               
                 cg21667878 
                 11 
                 2160980 
                 INS-IGF2; IGF2AS; IGF2; IGF2; IGF2AS; IGF2 
               
               
                 cg21692846 
                 11 
                 134146075 
                 GLB1L3 
               
               
                 cg21787291 
                 6 
                 124125170 
                 NKAIN2; NKAIN2 
               
               
                 cg21802055 
                 4 
                 4868794 
               
               
                 cg22007163 
                 6 
                 28602927 
               
               
                 cg22007227 
                 1 
                 32930544 
                 ZBTB8B 
               
               
                 cg22028075 
                 4 
                 6564820 
               
               
                 cg22031998 
                 19 
                 58609730 
                 ZSCAN18; ZSCAN18; ZSCAN18; ZSCAN18 
               
               
                 cg22091110 
                 18 
                 5630348 
               
               
                 cg22111078 
                 5 
                 172655925 
               
               
                 cg22152407 
                 20 
                 23030446 
                 THBD 
               
               
                 cg22212691 
                 2 
                 220417868 
                 OBSL1 
               
               
                 cg22263131 
                 6 
                 94129697 
                 EPHA7 
               
               
                 cg22276619 
                 8 
                 21645332 
                 GFRA2; GFRA2; GFRA2 
               
               
                 cg22284043 
                 13 
                 92051576 
                 GPC5 
               
               
                 cg22286978 
                 19 
                 58858806 
                 A1BG 
               
               
                 cg22298430 
                 17 
                 5404330 
                 LOC728392; LOC728392 
               
               
                 cg22321089 
                 13 
                 21649722 
               
               
                 cg22371972 
                 11 
                 22364961 
                 SLC17A6 
               
               
                 cg22413388 
                 22 
                 46367617 
                 WNT7B 
               
               
                 cg22459630 
                 15 
                 68121028 
                 LBXCOR1 
               
               
                 cg22474464 
                 20 
                 21492914 
                 NKX2-2 
               
               
                 cg22490134 
                 10 
                 22624847 
               
               
                 cg22546168 
                 10 
                 135050326 
                 VENTX 
               
               
                 cg22604123 
                 1 
                 32930522 
                 ZBTB8B 
               
               
                 cg22610211 
                 3 
                 139654264 
                 CLSTN2 
               
               
                 cg22623967 
                 3 
                 16554910 
                 RFTN1 
               
               
                 cg22630755 
                 5 
                 134871807 
                 NEUROG1 
               
               
                 cg22657780 
                 2 
                 180725907 
                 ZNF385B; MIR1258; ZNF385B 
               
               
                 cg22675486 
                 1 
                 165414544 
                 RXRG; RXRG 
               
               
                 cg22723056 
                 11 
                 7273378 
                 SYT9; SYT9 
               
               
                 cg22746058 
                 10 
                 23481176 
                 PTF1A 
               
               
                 cg22830113 
                 2 
                 127783168 
               
               
                 cg22863523 
                 11 
                 14995201 
                 CALCA; CALCA; CALCA 
               
               
                 cg22871002 
                 14 
                 62279623 
               
               
                 cg22876812 
                 2 
                 71116188 
               
               
                 cg22882665 
                 2 
                 45241110 
               
               
                 cg22901008 
                 10 
                 91295650 
                 SLC16A12 
               
               
                 cg22902266 
                 9 
                 96714313 
                 BARX1 
               
               
                 cg22903300 
                 6 
                 29760765 
                 HCG4 
               
               
                 cg22931182 
                 11 
                 44331623 
                 ALX4; ALX4 
               
               
                 cg22937649 
                 17 
                 8926794 
                 NTN1 
               
               
                 cg22955973 
                 3 
                 154797947 
                 MME; MME; MME; MME 
               
               
                 cg23010538 
                 1 
                 190447290 
                 FAM5C 
               
               
                 cg23018873 
                 11 
                 94501467 
                 AMOTL1 
               
               
                 cg23020486 
                 1 
                 236558874 
                 EDARADD; EDARADD; EDARADD 
               
               
                 cg23027580 
                 8 
                 67089513 
                 CRH 
               
               
                 cg23048481 
                 1 
                 39044196 
               
               
                 cg23080354 
                 22 
                 45405880 
                 PHF21B; PHF21B 
               
               
                 cg23154059 
                 2 
                 219736250 
                 WNT6 
               
               
                 cg23194354 
                 7 
                 3340459 
                 SDK1 
               
               
                 cg23236554 
                 5 
                 132947501 
                 FSTL4 
               
               
                 cg23242697 
                 8 
                 93115324 
               
               
                 cg23250494 
                 15 
                 78913474 
                 CHRNA3; CHRNA3; CHRNA3; CHRNA3 
               
               
                 cg23253569 
                 21 
                 34398222 
                 OLIG2 
               
               
                 cg23272632 
                 14 
                 77737146 
                 NGB 
               
               
                 cg23291854 
                 14 
                 88792913 
                 KCNK10; KCNK10 
               
               
                 cg23333915 
                 13 
                 95365509 
                 SOX21 
               
               
                 cg23363014 
                 6 
                 30227800 
                 HLA-L 
               
               
                 cg23391785 
                 1 
                 171810972 
                 DNM3; DNM3 
               
               
                 cg23415756 
                 17 
                 8925752 
                 NTN1 
               
               
                 cg23452969 
                 11 
                 62691182 
               
               
                 cg23477406 
                 12 
                 132312741 
                 MMP17 
               
               
                 cg23502778 
                 14 
                 27068135 
                 NOVA1; NOVA1; NOVA1 
               
               
                 cg23609571 
                 14 
                 70655845 
                 SLC8A3; SLC8A3; SLC8A3; SLC8A3 
               
               
                 cg23688510 
                 6 
                 166581929 
                 T; T 
               
               
                 cg23708361 
                 7 
                 145813432 
                 CNTNAP2 
               
               
                 cg23720732 
                 20 
                 44650380 
                 SLC12A5; SLC12A5 
               
               
                 cg23721712 
                 6 
                 30227967 
                 HLA-L 
               
               
                 cg23770904 
                 20 
                 61051561 
                 GATA5 
               
               
                 cg23808946 
                 2 
                 45169548 
                 SIX3 
               
               
                 cg23811464 
                 12 
                 24716204 
                 SOX5 
               
               
                 cg23906738 
                 14 
                 36987301 
                 NKX2-1; NKX2-1 
               
               
                 cg23936023 
                 5 
                 82769030 
                 VCAN; VCAN; VCAN; VCAN 
               
               
                 cg23991622 
                 10 
                 17271303 
                 VIM 
               
               
                 cg24034005 
                 14 
                 97059192 
               
               
                 cg24037897 
                 10 
                 16562626 
                 C1QL3 
               
               
                 cg24087887 
                 13 
                 39261432 
                 FREM2; FREM2 
               
               
                 cg24094550 
                 12 
                 54333565 
                 HOXC13 
               
               
                 cg24122124 
                 19 
                 5339092 
                 PTPRS; PTPRS; PTPRS; PTPRS 
               
               
                 cg24319171 
                 12 
                 187480 
                 IQSEC3; IQSEC3 
               
               
                 cg24320612 
                 20 
                 61051317 
                 GATA5 
               
               
                 cg24342409 
                 15 
                 92937992 
                 ST8SIA2 
               
               
                 cg24359323 
                 11 
                 69634372 
                 FGF3 
               
               
                 cg24395801 
                 1 
                 86622624 
                 COL24A1 
               
               
                 cg24400921 
                 12 
                 42984337 
                 PRICKLE1 
               
               
                 cg24446548 
                 7 
                 19157263 
                 TWIST1; TWIST1 
               
               
                 cg24453580 
                 12 
                 49691064 
                 PRPH 
               
               
                 cg24500900 
                 20 
                 61051423 
                 GATA5 
               
               
                 cg24534742 
                 13 
                 43149281 
                 TNFSF11; TNFSF11 
               
               
                 cg24565369 
                 7 
                 119913683 
                 KCND2 
               
               
                 cg24610236 
                 7 
                 30722114 
                 CRHR2; CRHR2 
               
               
                 cg24617696 
                 2 
                 121104312 
                 INHBB 
               
               
                 cg24632241 
                 2 
                 80530431 
                 CTNNA2; LRRTM1; CTNNA2 
               
               
                 cg24642320 
                 4 
                 186049687 
               
               
                 cg24662718 
                 1 
                 108507468 
                 VAV3 
               
               
                 cg24678137 
                 11 
                 7273735 
                 SYT9 
               
               
                 cg24686074 
                 10 
                 102497666 
               
               
                 cg24761507 
                 17 
                 35293930 
                 LHX1 
               
               
                 cg24767148 
                 10 
                 23481786 
                 PTF1A 
               
               
                 cg24792289 
                 5 
                 134825895 
               
               
                 cg24805239 
                 7 
                 24797486 
                 DFNA5; DFNA5; DFNA5; DFNA5; DFNA5 
               
               
                 cg24809973 
                 8 
                 72468820 
               
               
                 cg24876960 
                 5 
                 1883214 
                 IRX4 
               
               
                 cg24879782 
                 2 
                 19561482 
               
               
                 cg24880701 
                 15 
                 68121563 
                 LBXCOR1 
               
               
                 cg24886267 
                 5 
                 167956306 
                 FBLL1 
               
               
                 cg24890043 
                 2 
                 135476297 
                 TMEM163 
               
               
                 cg24908814 
                 5 
                 132947725 
                 FSTL4 
               
               
                 cg24937747 
                 5 
                 1882902 
                 IRX4 
               
               
                 cg24979348 
                 12 
                 15374303 
                 RERG; RERG 
               
               
                 cg24989739 
                 6 
                 105628027 
                 POPDC3 
               
               
                 cg25014318 
                 6 
                 39016776 
                 GLP1R 
               
               
                 cg25019648 
                 17 
                 72353261 
                 BTBD17 
               
               
                 cg25020286 
                 1 
                 18956947 
                 PAX7; PAX7; PAX7 
               
               
                 cg25075147 
                 2 
                 175547399 
                 WIPF1 
               
               
                 cg25082959 
                 13 
                 103046930 
                 FGF14 
               
               
                 cg25104105 
                 1 
                 14925198 
                 KIAA1026; KIAA1026 
               
               
                 cg25146017 
                 6 
                 110679400 
                 C6orf186 
               
               
                 cg25167643 
                 7 
                 121513538 
                 PTPRZ1; PTPRZ1 
               
               
                 cg25185881 
                 4 
                 156681047 
                 GUCY1B3 
               
               
                 cg25303599 
                 11 
                 61595807 
                 FADS2; FADS2 
               
               
                 cg25333258 
                 7 
                 44365029 
                 CAMK2B; CAMK2B; CAMK2B; CAMK2B; CAMK2B; CAMK2B; 
               
               
                   
                   
                   
                 CAMK2B; CAMK2B; CAMK2B; CAMK2B; CAMK2B; CAMK2B; 
               
               
                   
                   
                   
                 CAMK2B; CAMK2B; CAMK2B; CAMK2B 
               
               
                 cg25402610 
                 7 
                 127807500 
               
               
                 cg25446309 
                 10 
                 131770223 
               
               
                 cg25485192 
                 7 
                 94284439 
                 SGCE; SGCE; PEG10; SGCE; PEG10 
               
               
                 cg25531700 
                 12 
                 132312744 
                 MMP17 
               
               
                 cg25561581 
                 22 
                 45405899 
                 PHF21B; PHF21B 
               
               
                 cg25640822 
                 5 
                 134871645 
                 NEUROG1 
               
               
                 cg25649038 
                 6 
                 6546777 
                 LOC285780 
               
               
                 cg25662463 
                 10 
                 118897857 
                 VAX1; VAX1 
               
               
                 cg25669309 
                 4 
                 184826324 
                 STOX2 
               
               
                 cg25670060 
                 11 
                 98891544 
                 CNTN5; CNTN5 
               
               
                 cg25670330 
                 3 
                 138665984 
                 FOXL2; C3orf72 
               
               
                 cg25681339 
                 17 
                 1174148 
                 BHLHA9 
               
               
                 cg25723050 
                 1 
                 224804222 
                 CNIH3; CNIH3 
               
               
                 cg25730685 
                 1 
                 2375010 
               
               
                 cg25796439 
                 20 
                 13200939 
                 ISM1 
               
               
                 cg25805709 
                 3 
                 44596770 
                 ZNF167; ZNF167; ZNF167; ZNF167 
               
               
                 cg25830696 
                 17 
                 42030479 
                 PYY 
               
               
                 cg25848557 
                 1 
                 108507766 
                 VAV3 
               
               
                 cg25875213 
                 19 
                 38183055 
                 ZNF781; ZNF781 
               
               
                 cg25905674 
                 17 
                 43047856 
               
               
                 cg25920406 
                 10 
                 35929369 
                 FZD8 
               
               
                 cg25927708 
                 2 
                 119603813 
                 EN1 
               
               
                 cg25932164 
                 20 
                 37434950 
                 PPP1R16B 
               
               
                 cg25942031 
                 5 
                 178487410 
                 ZNF354C 
               
               
                 cg25964032 
                 10 
                 35929326 
                 FZD8 
               
               
                 cg25975712 
                 22 
                 48971051 
                 FAM19A5; FAM19A5 
               
               
                 cg26000619 
                 19 
                 2251067 
                 AMH 
               
               
                 cg26000663 
                 11 
                 26353723 
                 ANO3; ANO3 
               
               
                 cg26043257 
                 4 
                 15780238 
                 CD38 
               
               
                 cg26068551 
                 1 
                 57111117 
                 PRKAA2 
               
               
                 cg26072058 
                 1 
                 91191055 
               
               
                 cg26110710 
                 13 
                 88323607 
                 SLITRK5 
               
               
                 cg26114043 
                 4 
                 128544375 
               
               
                 cg26149275 
                 2 
                 176950007 
                 EVX2 
               
               
                 cg26150071 
                 1 
                 34629559 
                 CSMD2 
               
               
                 cg26170805 
                 18 
                 5630016 
               
               
                 cg26195812 
                 2 
                 27071332 
                 DPYSL5 
               
               
                 cg26224671 
                 13 
                 43148935 
                 TNFSF11; TNFSF11 
               
               
                 cg26261793 
                 1 
                 171810543 
                 DNM3; DNM3 
               
               
                 cg26271891 
                 2 
                 180726249 
                 ZNF385B; MIR1258 
               
               
                 cg26339504 
                 10 
                 118897859 
                 VAX1; VAX1 
               
               
                 cg26365854 
                 11 
                 44330903 
                 ALX4 
               
               
                 cg26432256 
                 14 
                 77607222 
                 ZDHHC22 
               
               
                 cg26466094 
                 1 
                 77748129 
                 AK5; AK5 
               
               
                 cg26477488 
                 5 
                 153858936 
                 HAND1 
               
               
                 cg26477573 
                 19 
                 15342915 
                 EPHX3; EPHX3 
               
               
                 cg26532358 
                 6 
                 118228871 
                 SLC35F1; SLC35F1 
               
               
                 cg26540367 
                 16 
                 215864 
                 HBM 
               
               
                 cg26541867 
                 4 
                 37246688 
                 KIAA1239 
               
               
                 cg26565021 
                 19 
                 34112825 
                 CHST8; CHST8 
               
               
                 cg26599006 
                 22 
                 19137371 
                 GSC2 
               
               
                 cg26608883 
                 11 
                 15095024 
                 CALCB 
               
               
                 cg26649384 
                 2 
                 154334651 
                 RPRM; RPRM 
               
               
                 cg26659805 
                 19 
                 2251588 
                 AMH 
               
               
                 cg26678605 
                 10 
                 118925011 
               
               
                 cg26692294 
                 5 
                 6449001 
                 UBE2QL1; UBE2QL1 
               
               
                 cg26705425 
                 19 
                 54024076 
                 ZNF331 
               
               
                 cg26708235 
                 13 
                 25946397 
                 ATPBA2 
               
               
                 cg26721193 
                 8 
                 93114951 
               
               
                 cg26721264 
                 18 
                 74961727 
                 GALR1 
               
               
                 cg26733786 
                 12 
                 65515034 
                 WIF1; WIF1 
               
               
                 cg26756083 
                 8 
                 89339622 
                 MMP16; MMP16; MMP16; MMP16 
               
               
                 cg26770917 
                 21 
                 34444339 
                 OLIG1; OLIG1 
               
               
                 cg26818735 
                 7 
                 19156621 
                 TWIST1 
               
               
                 cg26831241 
                 2 
                 175546916 
                 WIPF1 
               
               
                 cg26844246 
                 5 
                 170736277 
                 TLX3 
               
               
                 cg26886381 
                 13 
                 96296979 
                 DZIP1; DZIP1 
               
               
                 cg26961808 
                 7 
                 128470913 
                 FLNC; FLNC 
               
               
                 cg26976732 
                 16 
                 216100 
                 HBM 
               
               
                 cg26985666 
                 11 
                 35441088 
                 SLC1A2; SLC1A2 
               
               
                 cg26986911 
                 5 
                 33936292 
                 RXFP3 
               
               
                 cg26988895 
                 7 
                 6576353 
                 GRID2IP 
               
               
                 cg27034576 
                 10 
                 118031654 
                 GFRA1; GFRA1; GFRA1; GFRA1 
               
               
                 cg27037018 
                 5 
                 1445567 
                 SLC6A3 
               
               
                 cg27058257 
                 19 
                 30019529 
                 VSTM2B 
               
               
                 cg27066284 
                 17 
                 71161258 
                 SSTR2; SSTR2 
               
               
                 cg27101125 
                 19 
                 17392770 
                 ANKLE1 
               
               
                 cg27125849 
                 17 
                 59473674 
               
               
                 cg27205687 
                 11 
                 106888787 
                 GUCY1A2; GUCY1A2 
               
               
                 cg27237300 
                 21 
                 34442292 
                 OLIG1 
               
               
                 cg27304110 
                 1 
                 114695695 
                 SYT6 
               
               
                 cg27316886 
                 12 
                 3600106 
                 PRMT8 
               
               
                 cg27398263 
                 13 
                 79177700 
                 POU4F1 
               
               
                 cg27420520 
                 12 
                 103352267 
                 ASCL1 
               
               
                 cg27464184 
                 12 
                 114075881 
               
               
                 cg27486637 
                 4 
                 176987174 
                 WDR17; WDR17; WDR17; WDR17 
               
               
                 cg27493301 
                 12 
                 42982929 
                 PRICKLE1 
               
               
                 cg27510832 
                 1 
                 76080684 
               
               
                 cg27511255 
                 20 
                 47444851 
                 PREX1 
               
               
                 cg27545919 
                 19 
                 37157995 
                 ZNF461 
               
               
                 cg27547954 
                 1 
                 76081962 
               
               
                 cg27591450 
                 17 
                 75525004 
               
               
                 cg27605748 
                 5 
                 42951711 
               
               
                 cg27606567 
                 3 
                 44040811 
               
               
                 cg27628784 
                 10 
                 131767387 
               
               
                 cg27648738 
                 15 
                 84115811 
                 SH3GL3; SH3GL3 
               
               
                 cg27649239 
                 15 
                 68120393 
                 LBXCOR1 
               
               
                   
               
            
           
         
       
     
     Example 8: Narrowing Probes in Two Cohorts and Verification 
     The patient groups of Examples 1 and 2 were defined as Cohort 1 (C1) and Cohort 2 (C2), respectively, and the narrowing of probes to be used in analysis and the verification thereof were carried out according to the following procedures ( FIG. 16 ). 
     1) First, using the algorithm called Random Forest, prediction models regarding classification into HMCC and LMCC were produced.
 
2) From 3,163 probes extracted from Cohort 1 and 2,577 probes extracted from Cohort 2, 1,744 probes common in the two cohorts were extracted.
 
3) Using the extracted 1,744 probes, models were produced in C1 by performing Random Forest, and the classification results of C2 were then predicted.
 
4) Using the extracted 1,744 probes, models were produced in C2 by performing Random Forest, and the classification results of C1 were then predicted.
 
5) In the above 3) and 4), the importance of variables used in the production of models by Random Forests was confirmed, and such variables were narrowed to 0.002 or more.
 
6) As a result of the above 5), 140 probes were extracted from the C1 models and 128 probes were extracted from the C2 models.
 
7) In the above 6), when the common probes were extracted, 24 probes remained.
 
8) Using these 24 probes, the above predictions 3) and 4) were carried out.
 
8-1) When models were produced in C1 and the classification results of C2 were then predicted, the accuracy rate was found to be 98.1% (the answer was different from the correct answer only in one case).
 
8-2) When models were produced in C2 and the classification results of C1 were then predicted, the accuracy rate was found to be 100%.
 
     The extracted 24 probes are shown in Table 8. Using the 24 probes, the conditions shown in the slide were determined, and the 97 cases used in the analysis were classified again. The obtained results are shown in  FIG. 17 . In the present classification, when each probe has a β value of 0.5 or more, it was determined that the probe was methylation-positive. Moreover, among the 24 probes, when the number of methylation-positive probes was 16 or more, it was determined that the case was among an HMCC group, and when the number of methylation-positive probes was 15 or less, it was determined that the case was among an LMCC group. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Information of 24 genes 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Chromosome 
                 Location 
               
               
                 TargetID 
                 UCSC_REFGENE_NAME 
                 No. (chr) 
                 information 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 cg01791410 
                   
                 3 
                 150802997 
               
               
                 cg01802453 
                 ODZ3 
                 4 
                 183370148 
               
               
                 cg02484469 
                 GATA5 
                 20 
                 61051036 
               
               
                 cg02916312 
                 RIMS1 
                 6 
                 72596135 
               
               
                 cg03839709 
                 HS6ST3 
                 13 
                 96743492 
               
               
                 cg05218346 
                   
                 14 
                 70041283 
               
               
                 cg07005523 
                 NTNG1 
                 1 
                 107683187 
               
               
                 cg07068327 
                 GPR123 
                 10 
                 134901279 
               
               
                 cg07258916 
                 PLXNA4 
                 7 
                 132262353 
               
               
                 cg07360792 
                 PRDM6 
                 5 
                 122425702 
               
               
                 cg09767602 
                 ODZ3 
                 4 
                 183370138 
               
               
                 cg11092616 
                 RIMS1 
                 6 
                 72596493 
               
               
                 cg12646649 
                 LBX1 
                 10 
                 102987257 
               
               
                 cg13267931 
                 EMID2 
                 7 
                 101006308 
               
               
                 cg16041660 
                 PRICKLE1 
                 12 
                 42983360 
               
               
                 cg16958716 
                 PPM1E 
                 17 
                 56833425 
               
               
                 cg17188046 
                   
                 6 
                 166582197 
               
               
                 cg18412834 
                 FLJ16779; NKAIN4 
                 20 
                 61885291 
               
               
                 cg20012008 
                 AUTS2 
                 7 
                 69062534 
               
               
                 cg20265733 
                 GATA5 
                 20 
                 61051032 
               
               
                 cg20339230 
                 ST8SIA2 
                 15 
                 92937360 
               
               
                 cg21787291 
                 NKAIN2 
                 6 
                 124125170 
               
               
                 cg24792289 
                   
                 5 
                 134825895 
               
               
                 cg27628784 
                   
                 10 
                 131767387 
               
               
                   
               
               
                 * As a “reference” gene of location information, “hg19” was used. 
               
            
           
         
       
     
     In the table, each gene is specified with chromosome number and location information. 
     For example, when the chromosome number is 3 and location information is 150802997, it indicates that one specific nucleotide present at 150802997 of chromosome 3 has been methylated. Methylation in the present classification means that “one nucleotide in a specific site existing on the human genome has been methylated.” 
     Using the models produced in one cohort, the other cohort was classified. As a result, the accuracy rate was more than 90% in both of the cohorts. Accordingly, it was considered that the reproducibility of classification in each cohort is high, and that variables (probes) used in the classification of the two cohorts are constituted with those having similar tendency. Moreover, among the probes used for the models produced in each cohort, the common 24 probes were used, and models were produced again in each cohort by performing random forest. Thereafter, the other cohort was classified. As a result, all cases, except for one case, were accurately classified. 
     From the aforementioned results, it was demonstrated that, by using the extracted 24 probes, classification into HMCC or LMCC can be carried out with precision almost equivalent to the case of using 3,144 or 2,577 probes. 
     That is to say, it was demonstrated that conversion to a simple detection system, which is directed towards clinical application, is possible. 
     INDUSTRIAL APPLICABILITY 
     The method of the present invention has a small variation in the results caused by specimen collection conditions, and thus, even using a specimen collected upon excision of a primary lesion, the results equivalent to those of methylation profiles in the tumor at the time point of initiation of the treatment were obtained. Moreover, since the method of the present invention enables not only selection of a primary treatment and a secondary treatment in a combination therapy, but also determination of the suitability of the order in which these therapies are applied, the present method can provide the optimal therapeutic planning depending on the conditions of a patient or disease. That is to say, according to the present invention, the responsiveness of a patient to cancer drug therapy can be predicted with high precision, economical and/or physical burden on the patient are reduced, and administration guidelines with higher cost-effectiveness can be provided. 
     All publications, patents and patent applications cited in the present description are incorporated herein by reference in their entirety.