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1373649-03-Methods-p01 | [
"Peripheral",
"blood",
"was",
"collected",
"from",
"the",
"three",
"consulting",
"family",
"members",
"and",
"the",
"proband's",
"father.",
"Genomic",
"DNA",
"isolation",
"from",
"their",
"lymphocytes",
"was",
"performed",
"using",
"a",
"standard",
"phenol-chloroform",
"extraction.",
"DNA",
"from",
"the",
"proband",
"was",
"obtained",
"from",
"the",
"formalin-fixed,",
"paraffin",
"embedded",
"tissue",
"blocks",
"and",
"isolated",
"by",
"microdissection",
"of",
"tumor,",
"deparaffinization,",
"proteinase",
"K",
"treatment,",
"and",
"ethanol",
"precipitation",
"[7]."
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] | Peripheral blood was collected from the three consulting family members and the proband's father. Genomic DNA isolation from their lymphocytes was performed using a standard phenol-chloroform extraction. DNA from the proband was obtained from the formalin-fixed, paraffin embedded tissue blocks and isolated by microdissection of tumor, deparaffinization, proteinase K treatment, and ethanol precipitation [7]. |
1619718-01-Abstract-p01 | [
"Methods",
"and",
"results"
] | [
0,
0,
0
] | Methods and results |
2386495-05-Discussion-p04 | [
"Mutation-detection",
"frequency"
] | [
0,
0
] | Mutation-detection frequency |
2275286-01-Abstract-p01 | [
"In",
"146",
"prospectively",
"recruited",
"consecutive",
"patients",
"with",
"clinically",
"proven",
"colorectal",
"cancer,",
"MSI",
"carriers",
"were",
"identified",
"by",
"analysis",
"of",
"tumor",
"tissue",
"using",
"multiplex",
"fluorescence",
"polymerase",
"chain",
"reaction",
"(PCR)",
"using",
"the",
"NCI",
"recommended",
"panel",
"and",
"classified",
"into",
"microsatellite",
"instability-low",
"(MSI-L),",
"microsatellite",
"instability-high",
"(MSI-H)",
"and",
"microsatellite",
"stable",
"(MSS)",
"groups.",
"Immunohistochemical",
"staining",
"for",
"MSH2,",
"MSH6",
"and",
"MLH1",
"on",
"tissue",
"microarrays",
"(TMAs)",
"was",
"performed,",
"and",
"methylation",
"of",
"the",
"MLH1",
"promoter",
"was",
"analyzed",
"by",
"quantitative",
"methylation",
"specific",
"PCR",
"(MSP).",
"Germline",
"mutation",
"analysis",
"of",
"blood",
"samples",
"was",
"performed",
"for",
"MSH2,",
"MSH6",
"and",
"MLH1",
"genes."
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] | In 146 prospectively recruited consecutive patients with clinically proven colorectal cancer, MSI carriers were identified by analysis of tumor tissue using multiplex fluorescence polymerase chain reaction (PCR) using the NCI recommended panel and classified into microsatellite instability-low (MSI-L), microsatellite instability-high (MSI-H) and microsatellite stable (MSS) groups. Immunohistochemical staining for MSH2, MSH6 and MLH1 on tissue microarrays (TMAs) was performed, and methylation of the MLH1 promoter was analyzed by quantitative methylation specific PCR (MSP). Germline mutation analysis of blood samples was performed for MSH2, MSH6 and MLH1 genes. |
2275286-04-Results-p02 | [
"Clinical",
"features",
"of",
"patients",
"in",
"the",
"MSI",
"group",
"with",
"MMR",
"gene",
"mutations"
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] | Clinical features of patients in the MSI group with MMR gene mutations |
1266026-04-Results-p01 | [
"Duke's",
"stage",
"and",
"age",
"at",
"clinical",
"presentation",
"(Figure",
"1B)",
"were",
"documented",
"for",
"884",
"of",
"the",
"895",
"MSI-",
"sporadic",
"cancers",
"(Table",
"1).",
"Average",
"ages",
"were",
"68.6",
"years",
"for",
"stage",
"A,",
"69.0",
"years",
"for",
"stage",
"B,",
"65.2",
"years",
"for",
"stage",
"C,",
"and",
"65.4",
"years",
"for",
"stage",
"D.",
"The",
"most",
"likely",
"numbers",
"of",
"oncogenic",
"mutations",
"were",
"seven",
"for",
"stage",
"A",
"cancers,",
"eight",
"for",
"stage",
"B",
"cancers,",
"and",
"six",
"for",
"stage",
"C",
"or",
"D",
"cancers",
"(Table",
"1)."
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] | Duke's stage and age at clinical presentation (Figure 1B) were documented for 884 of the 895 MSI- sporadic cancers (Table 1). Average ages were 68.6 years for stage A, 69.0 years for stage B, 65.2 years for stage C, and 65.4 years for stage D. The most likely numbers of oncogenic mutations were seven for stage A cancers, eight for stage B cancers, and six for stage C or D cancers (Table 1). |
1601966-05-Conclusion-p01 | [
"**",
"IGNORE",
"LINE",
"**"
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] | ** IGNORE LINE ** |
1334229-05-Discussion-p02 | [
"The",
"K-ras",
"mutation",
"frequency",
"of",
"37%",
"is",
"in",
"accordance",
"with",
"reported",
"frequencies",
"of",
"30",
"to",
"60%",
"[33-43].",
"The",
"frequency",
"of",
"37%",
"of",
"truncating",
"mutations",
"in",
"the",
"mutation",
"cluster",
"region",
"of",
"APC",
" ",
"in",
"this",
"study,",
"however,",
"seems",
"low",
"in",
"comparison",
"to",
"the",
"general",
"assumption",
"that",
"most",
"colorectal",
"tumours",
"harbour",
"a",
"mutation",
"in",
"the",
"APC",
" ",
"gene.",
"When",
"only",
"reports",
"from",
"studies",
"on",
"sporadic",
"rather",
"than",
"familial",
"colorectal",
"cancer",
"or",
"colorectal",
"cancer",
"cell",
"lines",
"are",
"considered,",
"the",
"mutation",
"frequencies",
"are",
"lower",
"and",
"vary",
"between",
"30",
"and",
"70%",
"[17,44-49],",
"and",
"a",
"population-based",
"case-control",
"study",
"in",
"the",
"Netherlands",
"reported",
"a",
"32%",
"mutation",
"frequency",
"[50]."
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] | The K-ras mutation frequency of 37% is in accordance with reported frequencies of 30 to 60% [33-43]. The frequency of 37% of truncating mutations in the mutation cluster region of APC in this study, however, seems low in comparison to the general assumption that most colorectal tumours harbour a mutation in the APC gene. When only reports from studies on sporadic rather than familial colorectal cancer or colorectal cancer cell lines are considered, the mutation frequencies are lower and vary between 30 and 70% [17,44-49], and a population-based case-control study in the Netherlands reported a 32% mutation frequency [50]. |
2386495-05-Discussion-p04 | [
"The",
"61",
"different",
"APC",
"mutations",
"listed",
"in",
"Additional",
"file",
"2",
"were",
"identified",
"among",
"81",
"of",
"the",
"96",
"families",
"of",
"the",
"Swedish",
"Polyposis",
"Registry",
"that",
"were",
"screened",
"for",
"APC",
"mutations.",
"Fifteen",
"of",
"the",
"cases",
"shown",
"to",
"be",
"APC-mutation",
"negative",
"where",
"all",
"subjected",
"to",
"mutational",
"screening",
"of",
"the",
"MUTYH",
"gene",
"and",
"six",
"of",
"them",
"were",
"shown",
"to",
"carry",
"biallelic",
"MUTYH",
"mutations",
"(reported",
"in",
"Kanter",
"Smoler",
"et",
"al[31]).",
"The",
"overall",
"mutation-detection",
"rate",
"in",
"APC",
"and",
"MUTYH",
"among",
"the",
"families",
"in",
"our",
"study",
"was",
"thus",
"90%.",
"In",
"total,",
"84%",
"of",
"the",
"families",
"carried",
"APC",
"mutations",
"while",
"6%",
"where",
"positive",
"for",
"biallelic",
"MUTYH",
"mutations.",
"The",
"mutation-detection",
"rate",
"we",
"have",
"reached",
"in",
"this",
"study",
"is",
"notably",
"high.",
"In",
"fact,",
"a",
"disease-causing",
"mutation",
"was",
"detected",
"in",
"all",
"cases",
"who",
"presented",
"with",
"a",
"classical",
"FAP",
"phenotype",
"(except",
"for",
"family",
"1",
"Polyposis",
"mutation",
"reduced",
"APC",
"expression"
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] | The 61 different APC mutations listed in Additional file 2 were identified among 81 of the 96 families of the Swedish Polyposis Registry that were screened for APC mutations. Fifteen of the cases shown to be APC-mutation negative where all subjected to mutational screening of the MUTYH gene and six of them were shown to carry biallelic MUTYH mutations (reported in Kanter Smoler et al[31]). The overall mutation-detection rate in APC and MUTYH among the families in our study was thus 90%. In total, 84% of the families carried APC mutations while 6% where positive for biallelic MUTYH mutations. The mutation-detection rate we have reached in this study is notably high. In fact, a disease-causing mutation was detected in all cases who presented with a classical FAP phenotype (except for family 1 Polyposis mutation reduced APC expression |
2386495-02-Background-p02 | [
"**",
"IGNORE",
"LINE",
"**"
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] | ** IGNORE LINE ** |
2386495-05-Discussion-p02 | [] | [] | |
1360090-04-Discussion-p01 | [
"The",
"frequencies",
"of",
"BRAF",
"mutation",
"observed",
"in",
"MSI-",
"(4%)",
"and",
"MSI+",
"(39%)",
"tumors",
"in",
"the",
"present",
"study",
"compare",
"favourably",
"(5%",
"and",
"52%,",
"respectively)",
"to",
"those",
"reported",
"recently",
"in",
"another",
"large,",
"population-based",
"study",
"[17].",
"Although",
"BRAF",
"mutations",
"are",
"much",
"more",
"frequent",
"in",
"MSI+",
"tumors,",
"the",
"comparative",
"rarity",
"of",
"this",
"phenotype",
"means",
"that",
"a",
"considerable",
"proportion",
"occur",
"in",
"MSI-",
"tumors.",
"In",
"the",
"present",
"study,",
"43%",
"of",
"all",
"BRAF",
"mutations",
"occurred",
"in",
"MSI-",
"tumors",
"BRAF",
" ",
"mutation",
"frequencies",
"of",
"up",
"to",
"70β80%",
"have",
"been",
"reported",
"in",
"sporadic",
"MSI+,",
"CIMP+",
"and",
"MLH1-methylated",
"CRC",
"and",
"polyps",
"[7,8,15,16].",
"For",
"reasons",
"that",
"are",
"still",
"unclear,",
"BRAF",
"mutations",
"are",
"approximately",
"5β10-fold",
"more",
"frequent",
"in",
"tumors",
"that",
"have",
"characteristic",
"features",
"of",
"sporadic",
"MSI+",
"(ie.",
"MLH1",
"methylated)",
"and",
"CIMP+",
"phenotypes.",
"These",
"include",
"proximal",
"colon",
"location,",
"poor",
"differentiation,",
"mucinous",
"histology",
"and",
"infiltrating",
"lymphocytes",
"[13,19,20].",
"Interestingly",
"however,",
"in",
"the",
"present",
"study",
"BRAF",
"mutations",
"never",
"occurred",
"in",
"association",
"with",
"KRAS",
"mutation,",
"were",
"present",
"in",
"only",
"3%",
"of",
"CIMP-",
"tumors",
"and",
"showed",
"no",
"association",
"with",
"TP53",
"mutation",
"(Table",
"2).",
"The",
"observation",
"that",
"BRAF",
"mutations",
"occur",
"only",
"very",
"rarely",
"in",
"HNPCC-related",
"MSI+",
"CRC",
"demonstrates",
"that",
"defective",
"DNA",
"mismatch",
"repair",
"is",
"not",
"involved",
"in",
"causing",
"this",
"genetic",
"alteration."
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] | The frequencies of BRAF mutation observed in MSI- (4%) and MSI+ (39%) tumors in the present study compare favourably (5% and 52%, respectively) to those reported recently in another large, population-based study [17]. Although BRAF mutations are much more frequent in MSI+ tumors, the comparative rarity of this phenotype means that a considerable proportion occur in MSI- tumors. In the present study, 43% of all BRAF mutations occurred in MSI- tumors BRAF mutation frequencies of up to 70β80% have been reported in sporadic MSI+, CIMP+ and MLH1-methylated CRC and polyps [7,8,15,16]. For reasons that are still unclear, BRAF mutations are approximately 5β10-fold more frequent in tumors that have characteristic features of sporadic MSI+ (ie. MLH1 methylated) and CIMP+ phenotypes. These include proximal colon location, poor differentiation, mucinous histology and infiltrating lymphocytes [13,19,20]. Interestingly however, in the present study BRAF mutations never occurred in association with KRAS mutation, were present in only 3% of CIMP- tumors and showed no association with TP53 mutation (Table 2). The observation that BRAF mutations occur only very rarely in HNPCC-related MSI+ CRC demonstrates that defective DNA mismatch repair is not involved in causing this genetic alteration. |
1619718-04-Results-p02 | [
"With",
"respect",
"to",
"the",
"25",
"serrated",
"polyps",
"with",
"dysplasia,",
"only",
"five",
"occurred",
"in",
"the",
"proximal",
"colon",
"(up",
"to",
"the",
"splenic",
"flexure).",
"Two",
"of",
"these",
"had",
"BRAF",
"mutation",
"(both",
"Group",
"A)",
"and",
"two",
"had",
"KRAS",
"mutation",
"(both",
"Group",
"B).",
"Seven",
"of",
"the",
"11",
"BRAF",
"mutations",
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"in",
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"derived",
"from",
"the",
"left",
"colon",
"or",
"rectum",
"(remaining",
"two",
"polyps",
"with",
"BRAF",
"mutation",
"from",
"site",
"unknown).",
"The",
"three",
"Group",
"A",
"SAs",
"polyp",
"serrated",
"KRAS",
" ",
"mutation)",
"(Table",
"1).",
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"finding",
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"either",
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"or",
"KRAS",
"mutations",
"in",
"both",
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"(Figure",
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] | With respect to the 25 serrated polyps with dysplasia, only five occurred in the proximal colon (up to the splenic flexure). Two of these had BRAF mutation (both Group A) and two had KRAS mutation (both Group B). Seven of the 11 BRAF mutations occurred in polyps derived from the left colon or rectum (remaining two polyps with BRAF mutation from site unknown). The three Group A SAs polyp serrated KRAS mutation) (Table 1). The frequent finding of either BRAF or KRAS mutations in both types of serrated polyp indicated that MPs and SAs might be heterogeneous lesions. These 25 serrated polyps with dysplasia were therefore grouped differently. Group A polyps (n = 16) included a non-dysplastic serrated component and/or dysplastic epithelium in which the architectural and cytological changes were more reminiscent of HP than adenoma (Figure 1A,B). Group B polyps (n = 9) comprised serrated polyps in which the epithelial dysplasia appeared adenomatous (Figure 1C,D). BRAF mutation occurred in 10/16 Group A polyps but only 1/9 Group B polyps (P < 0.03). KRAS mutation occurred in only 3/16 Group A polyps but in 5/9 Group B polyps (P = 0.06). In each of the five Group B polyps with KRAS mutation, the adenomatous component showed both villous change and serration. |
3034663-03-Methods-p01 | [
"No",
"familial",
"history",
"of",
"cancer",
"was",
"available",
"from",
"the",
"control",
"group.",
"Patients",
"diagnosed",
"at",
"an",
"age",
"over",
"50",
"years",
"and",
"not",
"referred",
"to",
"Genetic",
"Counselling",
"Units",
"were",
"considered",
"as",
"sporadic",
"CRC.",
"Samples",
"from",
"sporadic",
"CRC",
"patients",
"were",
"obtained",
"from",
"the",
"Elche",
"University",
"Hospital",
"BioBank",
"and",
"the",
"Castellon",
"Provincial",
"Hospital",
"BioBank.",
"Written",
"consent",
"to",
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"included",
"in",
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"respective",
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"was",
"obtained",
"from",
"each",
"patient.",
"CRC",
"patients,",
"as",
"index",
"subjects",
"from",
"families",
"with",
"suspicion",
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"LS",
"that",
"attended",
"Genetic",
"Counselling",
"at",
"the",
"Cancer",
"Units",
"of",
"the",
"Elche",
"and",
"La",
"Fe",
"Hospitals,",
"were",
"recruited.",
"The",
"study",
"was",
"approved",
"by",
"the",
"Ethics",
"Committee",
"of",
"the",
"Elche",
"University",
"Hospital."
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] | No familial history of cancer was available from the control group. Patients diagnosed at an age over 50 years and not referred to Genetic Counselling Units were considered as sporadic CRC. Samples from sporadic CRC patients were obtained from the Elche University Hospital BioBank and the Castellon Provincial Hospital BioBank. Written consent to be included in the respective biobanks was obtained from each patient. CRC patients, as index subjects from families with suspicion of LS that attended Genetic Counselling at the Cancer Units of the Elche and La Fe Hospitals, were recruited. The study was approved by the Ethics Committee of the Elche University Hospital. |
1601966-03-Results-p08 | [] | [] | |
2275286-04-Results-p02 | [
"The",
"mutation",
"between",
"the",
"MSI-L",
"and",
"MSI-H"
] | [
0,
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] | The mutation between the MSI-L and MSI-H |
1601966-03-Results-p02 | [
"**",
"IGNORE",
"LINE",
"**"
] | [
0,
0,
0,
0
] | ** IGNORE LINE ** |
1619718-05-Discussion-p03 | [
"Inactivation",
"of",
"MLH1",
"and",
"TP53",
"is",
"associated",
"with",
"malignant",
"progression."
] | [
0,
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0,
0,
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0,
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0,
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] | Inactivation of MLH1 and TP53 is associated with malignant progression. |
3034663-03-Methods-p02 | [
"Statistical",
"analysis"
] | [
0,
0
] | Statistical analysis |
1619718-05-Discussion-p02 | [
"dysplastic",
"serrated",
"polyps:",
"MP",
"and",
"SA"
] | [
0,
0,
0,
0,
0,
0
] | dysplastic serrated polyps: MP and SA |
1334229-02-Background-p01 | [
"According",
"to",
"the",
"paradigm",
"for",
"colorectal",
"cancer",
"development,",
"mutations",
"in",
"the",
"APC",
"and",
"K-ras",
"are",
"thought",
"to",
"contribute",
"to",
"the",
"early",
"developmental",
"stages",
"of",
"colorectal",
" ",
"cancer",
"[3].",
"However,",
"a",
"recent",
"study",
"based",
"on",
"the",
"analysis",
"of",
"APC,",
"K-ras",
"and",
"TP53",
"genes",
"concluded",
"that",
"simultaneous",
"occurrence",
"of",
"all",
"three",
"genetic",
"alterations",
"is",
"rare",
"and",
"that",
"multiple",
"genetic",
"pathways",
"may",
"be",
"relevant",
"to",
"colorectal",
" ",
"cancer",
"[9]."
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] | According to the paradigm for colorectal cancer development, mutations in the APC and K-ras are thought to contribute to the early developmental stages of colorectal cancer [3]. However, a recent study based on the analysis of APC, K-ras and TP53 genes concluded that simultaneous occurrence of all three genetic alterations is rare and that multiple genetic pathways may be relevant to colorectal cancer [9]. |
1619718-05-Discussion-p01 | [] | [] | |
1360090-02-Background-p01 | [
"**",
"IGNORE",
"LINE",
"**"
] | [
0,
0,
0,
0
] | ** IGNORE LINE ** |
2386495-04-Results-p01 | [
"Mutation",
"spectrum",
"of",
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"(A)",
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"spectrum",
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"showing",
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" ",
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"seven",
" ",
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"we",
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"Thirty-two",
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"81",
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"(range,",
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"those",
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"mutations",
"outside",
"this",
"region",
"(P",
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"Available",
"data",
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"number",
"shows",
"that,",
"in",
"spite",
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"age",
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"diagnosis,",
"dense",
"polyposis",
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"The",
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"(",
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"32",
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" ",
"were",
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"diagnosis",
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"34.4",
"(range,",
"14β57)",
"years",
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"those",
"with",
"mutations",
"outside",
"this",
"region",
"(P",
"<",
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"Available",
"data",
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"polyp",
"number",
"shows",
"that,",
"in",
"spite",
"of",
"higher",
"age",
"at",
"diagnosis,",
"dense",
"polyposis",
"(>",
"1000)",
"only",
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"75%",
"in",
"those",
"with",
"mutations",
"between",
"codon",
"1250",
"and",
"1464.",
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"the",
"former",
"group",
"29%",
"(7",
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"24)",
"had",
"CRC",
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"diagnosis",
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"with",
"25%",
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"mutation",
"16%",
"mutations",
",",
"27",
"novel",
"and",
"34",
"recurrent,",
"were",
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"81",
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"the",
"96",
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"families",
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"as",
"shown",
"in",
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"files",
"1",
"and",
"2.",
"A",
"mutation",
"spectrum",
"displaying",
"the",
"distribution",
"between",
"novel",
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"previously",
"reported",
"mutations",
"is",
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"Figure",
"1.",
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"de",
"novo",
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" ",
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"Thirty-two",
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"81",
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"with",
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"(P",
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"Available",
"data",
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"number",
"shows",
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"spite",
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"higher",
"age",
"at",
"diagnosis,",
"dense",
"polyposis",
"(>",
"1000)",
"only",
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"30%",
"of",
"the",
"probands",
"compared",
"with",
"75%",
"in",
"those",
"with",
"mutations",
"between",
"codon",
"1250",
"and",
"1464.",
"In",
"the",
"former",
"group",
"29%",
"(7",
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"24)",
"had",
"CRC",
"at",
"diagnosis",
"compared",
"with",
"25%",
"(2",
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"group.",
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"mean",
"age",
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"was",
"46.6",
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"37.5",
"(range",
"26β49)",
"years,",
"respectively.",
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"total",
"morbidity",
"in",
"CRC",
"among",
"probands",
"was",
"34%",
"(11",
"out",
"of",
"32).",
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"all",
"probands",
"diagnosed",
"after",
"1996,",
"four",
"out",
"of",
"nine",
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"had",
"cancer",
"at",
"diagnosis.",
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"median",
"age",
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"this",
"group",
"was",
"47.5",
"(range",
"45β51)",
"years",
"and",
"none",
"had,",
"despite",
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"age",
"at",
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"CRC,",
"dense",
"colorectal",
"polyposis",
"2",
"out",
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")",
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"group.",
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"mean",
"age",
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"CRC",
"was",
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"37.5",
"(range",
"26β49)",
"years,",
"respectively.",
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"in",
"CRC",
"among",
"probands",
"was",
"34%",
"(11",
"out",
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"32).",
"Of",
"all",
"probands",
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"1996,",
"four",
"out",
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"nine",
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"had",
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] | Mutation spectrum of the APC gene. (A) The spectrum of APC mutations identified among families from the Swedish Polyposis Registry showing the distribution between previously reported and novel mutations in our patients. (B) A schematic representation of the APC coding region, shown in the same scale as in (A). The arrow with an asterisk indicates codon 24 and the second arrow points at codon 184. (C) Distribution of six 29% 75% in those with mutations between codon 1250 and 1464. In the former group 29% (7 out of 24) had CRC at diagnosis compared with 25% (2 out of 8) in the latter group. The mean age at CRC was 46.6 (range 28β57) and 37.5 (range 26β49) years, respectively. The total morbidity in CRC among probands was 34% seven families we where unable to obtain samples to test parents. Thirty-two of the 81 patients with APC mutations were probands. Probands with mutations in the region from codon 1250 to 1464 of the APC gene which predicts a severe phenotype [36] had a median age at diagnosis of 21.8 (range, 11β49) years compared with 34.4 (range, 14β57) years among those with mutations outside this region (P < 0.017). Available data on colorectal polyp number shows that, in spite of higher age at diagnosis, dense polyposis (> 1000) only occurred in 30% of the probands compared with 75% in those with mutations between codon 1250 and 1464. In the former group 29% (7 out of 24) had CRC at diagnosis compared with 25% (2 out of 8) in the latter group. The mean age at CRC was 46.6 (range 28β57) and 37.5 (range 26β49) years, respectively. The total morbidity in CRC among probands was 34% ( 11 out of 32 mutations were probands. Probands with mutations in the region from codon 1250 to 1464 of the APC gene which predicts a severe phenotype [36] had a median age at diagnosis of 21.8 (range, 11β49) years compared with 34.4 (range, 14β57) years among those with mutations outside this region (P < 0.017). Available data on colorectal polyp number shows that, in spite of higher age at diagnosis, dense polyposis (> 1000) only occurred in 30% of the probands compared with 75% in those with mutations between codon 1250 and 1464. In the former group 29% (7 out of 24) had CRC at diagnosis compared with 25% probands mutation 16% mutations , 27 novel and 34 recurrent, were detected among 81 of the 96 Swedish families studied as shown in Additional files 1 and 2. A mutation spectrum displaying the distribution between novel and previously reported mutations is shown in Figure 1. The frequency of APC de novo mutation cases among the families was 16%. In three of the families parents were tested negative for the mutation and in the remaining seven families we where unable to obtain samples to test parents. Thirty-two of the 81 patients with APC mutations were probands. Probands with mutations in the region from codon 1250 to 1464 of the APC gene which predicts a severe phenotype [36] had a median age at diagnosis of 21.8 (range, 11β49) years compared with 34.4 (range, 14β57) years among those with mutations outside this region (P < 0.017). Available data on colorectal polyp number shows that, in spite of higher age at diagnosis, dense polyposis (> 1000) only occurred in 30% of the probands compared with 75% in those with mutations between codon 1250 and 1464. In the former group 29% (7 out of 24) had CRC at diagnosis compared with 25% (2 out of 8) in the latter group. The mean age at CRC was 46.6 (range 28β57) and 37.5 (range 26β49) years, respectively. The total morbidity in CRC among probands was 34% (11 out of 32). Of all probands diagnosed after 1996, four out of nine (44%) had cancer at diagnosis. The median age in this group was 47.5 (range 45β51) years and none had, despite high age at diagnosis of CRC, dense colorectal polyposis 2 out of 8 ) in the latter group. The mean age at CRC was 46.6 (range 28β57) and 37.5 (range 26β49) years, respectively. The total morbidity in CRC among probands was 34% (11 out of 32). Of all probands diagnosed after 1996, four out of nine (44%) had cancer at diagnosis. The median age in this group was 47.5 (range 45β51) years and none had, despite high age at diagnosis of CRC, dense colorectal polyposis at diagnosis indicating a less-severe phenotype. A compilation of clinical status of all patients analyzed in this study is shown in Additional file 1. |
1334229-05-Discussion-p02 | [
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1619718-04-Results-p03 | [
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2386495-05-Discussion-p04 | [
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1557864-01-Abstract-p01 | [
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1601966-03-Results-p10 | [
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1266026-05-Discussion-p02 | [
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"in",
"a",
"single",
"normal",
"appearing",
"cell.",
"In",
"this",
"way",
"our",
"multistage",
"model",
"can",
"apply",
"to",
"both",
"MSI+",
"and",
"MSI-",
"cancers",
"despite",
"their",
"marked",
"differences",
"in",
"types",
"of",
"mutations",
"because",
"early",
"critical",
"mutations",
"(whatever",
"they",
"are)",
"do",
"not",
"visibly",
"change",
"phenotype",
"but",
"instead",
"accumulate",
"in",
"normal",
"appearing",
"tumor",
"cancer",
"\"",
"mutations",
"may",
"first",
"accumulate",
"in",
"normal-appearing",
"colon",
"very",
"early",
"in",
"life.",
"Such",
"pretumor",
"progression",
"[11]",
"more",
"readily",
"allows",
"for",
"an",
"invasive",
"or",
"metastatic",
"cancer",
"phenotype",
"at",
"transformation",
"because",
"genetic",
"progression",
"is",
"uncoupled",
"from",
"tumor",
"cancers",
" ",
"[26-28]."
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] | In contrast, mutations accumulate throughout life in multistage models. Genetically engineered mice and familial cancer syndromes reveal that many oncogenic mutations are also compatible with normal phenotypes [11], allowing for the possibility that many "cancer" mutations may first accumulate in normal-appearing colon very early in life. Such pretumor progression [11] more readily allows for an invasive or metastatic cancer phenotype at transformation because genetic progression is uncoupled from tumor progression (Figure 2). Rather than incremental stepwise changes in phenotype after each new mutation, a tumor phenotype may only emerge after several initially occult mutations accumulate in a single normal appearing cell. In this way our multistage model can apply to both MSI+ and MSI- cancers despite their marked differences in types of mutations because early critical mutations (whatever they are) do not visibly change phenotype but instead accumulate in normal appearing tumor cancer " mutations may first accumulate in normal-appearing colon very early in life. Such pretumor progression [11] more readily allows for an invasive or metastatic cancer phenotype at transformation because genetic progression is uncoupled from tumor cancers [26-28]. |
1360090-04-Discussion-p01 | [
"Similar",
"to",
"other",
"studies",
"[4,5,10,16,17]",
"we",
"observed",
"BRAF",
"mutation",
"frequencies",
"of",
"4%",
"in",
"MSI-",
"tumors",
"and",
"39%",
"in",
"MSI+",
"tumors",
"(Table",
"1).",
"The",
"highest",
"frequencies",
"were",
"seen",
"in",
"tumors",
"showing",
"methylation",
"of",
"the",
"MLH1",
"promoter",
"proximal",
"region",
"(46%)",
"and",
"in",
"tumors",
"with",
"infiltrating",
"lymphocytes",
"(48%).",
"BRAF",
"mutation",
"frequencies",
"of",
"up",
"to",
"70β80%",
"have",
"been",
"reported",
"in",
"sporadic",
"MSI+,",
"CIMP+",
"and",
"MLH1-methylated",
"CRC",
"and",
"polyps",
"[7,8,15,16].",
"For",
"reasons",
"that",
"are",
"still",
"unclear,",
"BRAF",
"mutations",
"are",
"approximately",
"5β10-fold",
"more",
"frequent",
"in",
"tumors",
"that",
"have",
"characteristic",
"features",
"of",
"sporadic",
"MSI+",
"(ie.",
"MLH1",
"methylated)",
"and",
"CIMP+",
"phenotypes.",
"These",
"include",
"proximal",
"colon",
"location,",
"poor",
"differentiation,",
"mucinous",
"histology",
"and",
"infiltrating",
"lymphocytes",
"[13,19,20].",
"Interestingly",
"however,",
"in",
"the",
"present",
"study",
"BRAF",
"mutations",
"never",
"occurred",
"in",
"association",
"with",
"KRAS",
"mutation,",
"were",
"present",
"in",
"only",
"3%",
"of",
"CIMP-",
"tumors",
"and",
"showed",
"no",
"association",
"with",
"TP53",
"mutation",
"(Table",
"2).",
"The",
"observation",
"that",
"BRAF",
"mutations",
"occur",
"only",
"very",
"rarely",
"in",
"HNPCC-related",
"MSI+",
"CRC",
"demonstrates",
"that",
"defective",
"DNA",
"mismatch",
"repair",
"is",
"not",
"involved",
"in",
"causing",
"this",
"genetic",
"alteration."
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] | Similar to other studies [4,5,10,16,17] we observed BRAF mutation frequencies of 4% in MSI- tumors and 39% in MSI+ tumors (Table 1). The highest frequencies were seen in tumors showing methylation of the MLH1 promoter proximal region (46%) and in tumors with infiltrating lymphocytes (48%). BRAF mutation frequencies of up to 70β80% have been reported in sporadic MSI+, CIMP+ and MLH1-methylated CRC and polyps [7,8,15,16]. For reasons that are still unclear, BRAF mutations are approximately 5β10-fold more frequent in tumors that have characteristic features of sporadic MSI+ (ie. MLH1 methylated) and CIMP+ phenotypes. These include proximal colon location, poor differentiation, mucinous histology and infiltrating lymphocytes [13,19,20]. Interestingly however, in the present study BRAF mutations never occurred in association with KRAS mutation, were present in only 3% of CIMP- tumors and showed no association with TP53 mutation (Table 2). The observation that BRAF mutations occur only very rarely in HNPCC-related MSI+ CRC demonstrates that defective DNA mismatch repair is not involved in causing this genetic alteration. |
3034663-05-Discussion-p01 | [
"Unfortunately,",
"genetic",
"testing",
"for",
"hereditary",
"cancer",
"frequently",
"fails",
"to",
"identify",
"unambiguous",
"deleterious",
"variants.",
"Erroneous",
"classification",
"of",
"a",
"genetic",
"variant",
"may",
"have",
"a",
"great",
"effect",
"on",
"at-risk",
"familial",
"who",
"undergo",
"genetic",
"testing",
"for",
"risk",
"prediction",
"because",
"it",
"results",
"in",
"incorrect",
"clinical",
"recommendations."
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] | Unfortunately, genetic testing for hereditary cancer frequently fails to identify unambiguous deleterious variants. Erroneous classification of a genetic variant may have a great effect on at-risk familial who undergo genetic testing for risk prediction because it results in incorrect clinical recommendations. |
3034663-03-Methods-p01 | [
"The",
"median",
"age",
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"patients",
"in",
"the",
"sporadic",
"CRC",
"group",
"was",
"70",
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"52-93",
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"47",
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"21-87",
"years)",
"for",
"the",
"familial",
"Patients",
"1034",
" ",
"individuals",
"(373",
"sporadic",
"CRC",
"patients,",
"250",
"index",
"subjects",
"from",
"families",
"suspected",
"of",
"having",
"LS",
"[revised",
"Bethesda",
"Guidelines]",
"and",
"411",
"controls).",
"The",
"controls",
"were",
"selected",
"from",
"the",
"same",
"hospitals,",
"had",
"no",
"personal",
"histories",
"of",
"cancer",
"and",
"had",
"diagnoses",
"unrelated",
"to",
"the",
"variables",
"of",
"interest.",
"They",
"were",
"matched",
"for",
"age,",
"gender",
"and",
"race/ethnicity",
"with",
"the",
"sporadic",
"CRC",
"patients."
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] | The median age of patients in the sporadic CRC group was 70 years (range, 52-93 years), 47 years (range, 21-87 years) for the familial Patients 1034 individuals (373 sporadic CRC patients, 250 index subjects from families suspected of having LS [revised Bethesda Guidelines] and 411 controls). The controls were selected from the same hospitals, had no personal histories of cancer and had diagnoses unrelated to the variables of interest. They were matched for age, gender and race/ethnicity with the sporadic CRC patients. |
3034663-04-Results-p01 | [
"In",
"the",
"second",
"LS",
"family,",
"the",
"index",
"subject",
"11/411",
",",
"2.68%),",
"nine",
"were",
"CRC",
"patients",
"from",
"the",
"sporadic",
"group",
"(9/373,",
"2.41%)",
"and",
"seven",
"were",
"CRC",
"patients",
"from",
"the",
"familial",
"group",
"(7/250,",
"2.8%).",
"None",
"of",
"the",
"individuals",
"was",
"homozygous",
"for",
"the",
"minor",
"allele."
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] | In the second LS family, the index subject 11/411 , 2.68%), nine were CRC patients from the sporadic group (9/373, 2.41%) and seven were CRC patients from the familial group (7/250, 2.8%). None of the individuals was homozygous for the minor allele. |
1619718-05-Discussion-p04 | [
"Loss",
"of",
"expression",
"of",
"the",
"DNA",
"repair",
"gene",
"MGMT",
"is",
"associated",
"with",
"methylation",
"of",
"the",
"promoter",
"region45,51,52",
"and",
"the",
"latter",
"change",
"has",
"been",
"linked",
"causatively",
"with",
"G:C",
"to",
"A:T",
"transition",
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"in",
"TP53.53",
"In",
"the",
"present",
"study,",
"complete",
"or",
"partial",
"loss",
"of",
"expression",
"of",
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"coincided",
"with",
"aberrant",
"nuclear",
"expression",
"of",
"p53",
"in",
"three",
"serrated",
"polyps",
"with",
"dysplasia",
"(Figure",
"2),",
"but",
"not",
"in",
"the",
"single",
"tubular",
"adenoma",
"with",
"aberrant",
"p53",
"expression.",
"Only",
"one",
"previous",
"study",
"has",
"attempted",
"to",
"correlate",
"MGMT",
"and",
"p53",
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"in",
"colorectal",
"polyps.45",
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"that",
"study,",
"4.3%",
"of",
"adenomas",
"showed",
"aberrant",
"p53",
"expression",
"but",
"none",
"had",
"loss",
"of",
"MGMT.",
"It",
"is",
"possible",
"that",
"the",
"link",
"between",
"MGMT",
"silencing",
"and",
"TP53",
"mutation",
"is",
"more",
"evident",
"in",
"the",
"serrated",
"pathway",
"than",
"in",
"the",
"adenomaβcarcinoma",
"sequence.",
"The",
"frequency",
"of",
"TP53",
"mutation",
"in",
"SAs",
"has",
"ranged",
"from",
"5",
"to",
"50%",
"in",
"the",
"literature.39,41,54",
"Although",
"a",
"link",
"between",
"MGMT",
"loss",
"and",
"aberrant",
"expression",
"of",
"p53",
"is",
"supported",
"by",
"the",
"present",
"findings,",
"it",
"should",
"be",
"noted",
"that",
"only",
"a",
"small",
"number",
"of",
"polyps",
"showed",
"these",
"changes",
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] | Loss of expression of the DNA repair gene MGMT is associated with methylation of the promoter region45,51,52 and the latter change has been linked causatively with G:C to A:T transition mutations in TP53.53 In the present study, complete or partial loss of expression of MGMT coincided with aberrant nuclear expression of p53 in three serrated polyps with dysplasia (Figure 2), but not in the single tubular adenoma with aberrant p53 expression. Only one previous study has attempted to correlate MGMT and p53 expression in colorectal polyps.45 In that study, 4.3% of adenomas showed aberrant p53 expression but none had loss of MGMT. It is possible that the link between MGMT silencing and TP53 mutation is more evident in the serrated pathway than in the adenomaβcarcinoma sequence. The frequency of TP53 mutation in SAs has ranged from 5 to 50% in the literature.39,41,54 Although a link between MGMT loss and aberrant expression of p53 is supported by the present findings, it should be noted that only a small number of polyps showed these changes concurrently. |
2386495-04-Results-p02 | [
"DNA",
"sequencing",
"of",
"APC",
"exon",
"1",
"in",
"patient",
"patient",
"patient",
"patient",
"patient",
"patient",
" ",
"C107,",
"aberrant",
"bands,",
"possibly",
"originating",
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"formation",
"of",
"heteroduplexes,",
"was",
"detected",
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"SSCP/HD",
"in",
"a",
"very",
"low",
"fraction",
"of",
"her",
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"which",
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"frame",
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"at",
"codon",
"900,",
"was",
"found",
"by",
"sequencing",
"of",
"the",
"aberrant",
"bands",
"excised",
"from",
"the",
"SSCP/HD",
"gel",
"(Figure",
"2A).",
"The",
"mutation",
"was",
"detected",
"in",
"approximately",
"one-third",
"of",
"the",
"analyzed",
"tumor-derived",
"cells",
"extracted",
"from",
"paraffin-embedded",
"tissue",
"by",
"DNA",
"sequencing",
"(Figure",
"2B).",
"The",
"mutation",
"was",
"not",
"detectable",
"at",
"all",
"in",
"the",
"sequence",
"determination",
"of",
"DNA",
"extracted",
"from",
"blood",
"lymphocytes",
"from",
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"patient",
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] | DNA sequencing of APC exon 1 in patient patient patient patient patient patient C107, aberrant bands, possibly originating from formation of heteroduplexes, was detected by SSCP/HD in a very low fraction of her blood lymphocytes . The c.2700_2701delTC mutation, which results in frame shift at codon 900, was found by sequencing of the aberrant bands excised from the SSCP/HD gel (Figure 2A). The mutation was detected in approximately one-third of the analyzed tumor-derived cells extracted from paraffin-embedded tissue by DNA sequencing (Figure 2B). The mutation was not detectable at all in the sequence determination of DNA extracted from blood lymphocytes from the patient (Figure 2C). |
2275286-01-Abstract-p01 | [
"In",
"146",
"prospectively",
"recruited",
"consecutive",
"patients",
"with",
"clinically",
"proven",
"colorectal",
"cancer,",
"MSI",
"carriers",
"were",
"identified",
"by",
"analysis",
"of",
"tumor",
"tissue",
"using",
"multiplex",
"fluorescence",
"polymerase",
"chain",
"reaction",
"(PCR)",
"using",
"the",
"NCI",
"recommended",
"panel",
"and",
"classified",
"into",
"microsatellite",
"instability-low",
"(MSI-L),",
"microsatellite",
"instability-high",
"(MSI-H)",
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"microsatellite",
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"Germline",
"mutation",
"analysis",
"of",
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"was",
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"MSH2,",
"MSH6",
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] | In 146 prospectively recruited consecutive patients with clinically proven colorectal cancer, MSI carriers were identified by analysis of tumor tissue using multiplex fluorescence polymerase chain reaction (PCR) using the NCI recommended panel and classified into microsatellite instability-low (MSI-L), microsatellite instability-high (MSI-H) and microsatellite stable (MSS) groups. Immunohistochemical staining for MSH2, MSH6 and MLH1 on tissue microarrays (TMAs) was performed, and methylation of the MLH1 promoter was analyzed by quantitative methylation specific PCR (MSP). Germline mutation analysis of blood samples was performed for MSH2, MSH6 and MLH1 genes. |
2386495-05-Discussion-p04 | [
"The",
"61",
"different",
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"mutations",
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"2",
"were",
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"96",
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"Registry",
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"Fifteen",
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"where",
"all",
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"MUTYH",
"among",
"the",
"families",
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"our",
"study",
"was",
"thus",
"90%.",
"In",
"total,",
"84%",
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] | The 61 different APC mutations listed in Additional file 2 were identified among 81 of the 96 families of the Swedish Polyposis Registry that were screened for APC mutations. Fifteen of the cases shown to be APC-mutation negative where all subjected to mutational screening of the MUTYH gene and six of them were shown to carry biallelic MUTYH mutations (reported in Kanter Smoler et al[31]). The overall mutation-detection rate in APC and MUTYH among the families in our study was thus 90%. In total, 84% MLH1 APC APC expression |
1373649-03-Methods-p01 | [
"Study",
"protocol"
] | [
0,
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] | Study protocol |
2386495-04-Results-p05 | [
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"IGNORE",
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2386495-04-Results-p01 | [
"**",
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2275286-01-Abstract-p01 | [
"Thirty-four",
"out",
"of",
"the",
"146",
"colorectal",
"cancers",
"(CRCs,",
"23.2%)",
"were",
"MSI,",
"including",
"19",
"MSI-H",
"CRCs",
"and",
"15",
"MSI-L",
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"negative",
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"MSH6",
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"was",
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"MSH2.",
"Seventeen",
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"stained",
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"MLH1.",
"MLH1",
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"methylation",
"was",
"determined",
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"34",
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"CRCs.",
"Hypermethylation",
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"the",
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"CRCs",
"and",
"5",
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"34",
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"12",
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"5",
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"were",
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] | Thirty-four out of the 146 colorectal cancers (CRCs, 23.2%) were MSI, including 19 MSI-H CRCs and 15 MSI-L CRCS. Negative staining for MSH2 was found in 8 CRCs, negative staining for MSH6 was found in 6 CRCs. One MSI-H CRC was negative for both MSH6 and MSH2. Seventeen CRCs stained negatively for MLH1. MLH1 promoter methylation was determined in 34 MSI CRCs. Hypermethylation of the MLH1 promoter occurred in 14 (73.7%) out of 19 MSI-H CRCs and 5 (33.3%) out of 15 MSI-L CRCs. Among the 34 MSI carriers and one MSS CRC with MLH1 negative staining, 8 had a MMR gene germline mutation, which accounted for 23.5% of all MSI colorectal cancers and 5.5% of all the colorectal cancers. Five patients harbored MSH2 germline mutations, and three patients harbored MSH6 germline mutations. None of the patients had an MLH1 mutation. Mutations were commonly located in exon 7 and 12 of MSH2 and exon 5 of MSH6. Right colonic lesions and mucinous carcinoma were not common in MSI carriers. |
1619718-04-Results-p01 | [
"Frequency",
"of",
"KRAS",
"and",
"BRAF",
"mutation",
"and",
"loss",
"of",
"expression",
"of",
"O-6-methylguanine",
"DNA",
"methyltransferase",
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"by",
"polyp",
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] | Frequency of KRAS and BRAF mutation and loss of expression of O-6-methylguanine DNA methyltransferase (MGMT) by polyp type |
2386495-01-Abstract-p01 | [
"Abstract"
] | [
0
] | Abstract |
3034663-05-Discussion-p02 | [
"The",
"molecular",
"hallmark",
"of",
"LS",
"tumours",
"is",
"an",
"MSI",
"phenotype,",
"a",
"functional",
"consequence",
"of",
"MMR",
"deficiency.",
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"is",
"expected",
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"the",
"putative",
"germ-line",
"mutation",
"responsible",
"for",
"LS",
"would",
"confer",
"the",
"MSI",
"phenotype.",
"We",
"tested",
"the",
"MSI",
"status",
"of",
"17",
"tumours",
" ",
"from",
"p.Lys618Ala",
"carriers",
"and",
"detected",
"only",
"two",
"cases",
" ",
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"the",
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"in",
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"CRC",
"group",
"affected",
" ",
"and",
"informative",
"unaffected",
"individuals.",
"Moreover,",
"LS",
"deleterious",
"variants",
"are",
"not",
"completely",
"penetrant.",
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"these",
"reasons,",
"it",
"is",
"rarely",
"possible",
"to",
"categorize",
"variants",
"as",
"deleterious",
"based",
"on",
"segregation",
"alone.",
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"co-occurrence",
"of",
"another",
"known",
"deleterious",
"variant",
"reduces",
"the",
"likelihood",
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"an",
"UV",
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"truly",
"deleterious,",
"especially",
"when",
"both",
"variants",
"are",
"located",
"in",
"trans",
"[3].",
"To",
"our",
"knowledge,",
"co-occurrence",
"of",
"a",
"deleterious",
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"the",
"LS",
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"variant",
"has",
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"observed",
"in",
"only",
"two",
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"Liu",
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"al",
"[14]",
"described",
"an",
"index",
"subject",
"from",
"a",
"LS",
"family",
"with",
"two",
"heterozygous",
"variants",
"(c.546-2A>G",
"and",
"c.1852_1853AA>GC);",
"only",
"the",
"former",
"segregated",
"with",
"LS",
"in",
"the",
"family.",
"Similarly,",
"Steinke",
"et",
"al",
"[15],",
"described",
"the",
"co-occurrence",
"of",
"the",
"p.Lys618Ala",
"(c.1852_1853AA>GC)",
"variant",
"with",
"the",
"MSH6",
"p.Arg1068X",
"(c.3202C>T)",
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] | The molecular hallmark of LS tumours is an MSI phenotype, a functional consequence of MMR deficiency. It is expected that the putative germ-line mutation responsible for LS would confer the MSI phenotype. We tested the MSI status of 17 tumours from p.Lys618Ala carriers and detected only two cases of MSI (11.8%). Taking into consideration the bias caused by the over-representation of Bethesda Criteria-positive tumours in this subset of cases (8/17), the MSI frequency was not significantly different from that in the unselected CRC group affected and informative unaffected individuals. Moreover, LS deleterious variants are not completely penetrant. For these reasons, it is rarely possible to categorize variants as deleterious based on segregation alone. The co-occurrence of another known deleterious variant reduces the likelihood that an UV is truly deleterious, especially when both variants are located in trans [3]. To our knowledge, co-occurrence of a deleterious variant in one of the LS genes with the p.Lys618Ala variant has been observed in only two families. Liu et al [14] described an index subject from a LS family with two heterozygous variants (c.546-2A>G and c.1852_1853AA>GC); only the former segregated with LS in the family. Similarly, Steinke et al [15], described the co-occurrence of the p.Lys618Ala (c.1852_1853AA>GC) variant with the MSH6 p.Arg1068X (c.3202C>T) deleterious variant. |
1360090-03-Results-p01 | [
"Associations",
"between",
"BRAF",
"cases",
",",
"tumor",
"site",
"in",
"56",
"cases,",
"grade",
"in",
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1601966-06-Methods-p05 | [
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1334229-02-Background-p01 | [] | [] | |
1266026-04-Results-p01 | [
"Ages",
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"to",
"estimate",
"likely",
"numbers",
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"oncogenic",
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"and",
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"67.5,",
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"For",
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"estimated",
"numbers",
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] | Ages at cancer can be used to estimate likely numbers of oncogenic mutations required before transformation [3-6,11]. Average ages for sporadic MSI+, MSI-, and HNPCC cancers were respectively 71.5, 67.5, and 50.3 years (Figure 1A). For HNPCC cancers, estimated numbers of oncogenic mutations were between four and seven (95% credibility interval), with the most likely value of five mutations (Table 1). For MSI+ sporadic cancers, estimated numbers of mutations were between six and nine (95% credibility interval) with more likely values of seven or eight mutations. The most likely number of mutations was seven for sporadic MSI- cancers. |
1619718-05-Discussion-p02 | [
"Serrated",
"polyps",
"with",
"dysplasia,",
"i.e.",
"MPs",
"and",
"SAs,",
"together",
"comprised",
"only",
"2%",
"of",
"the",
"overall",
"consecutive",
"series",
"of",
"1250",
"polyps.",
"While",
"mutation",
"of",
"KRAS",
"and",
"BRAF",
"was",
"associated",
"with",
"conventional",
"adenoma",
"and",
"SSA,",
"respectively",
"(see",
"above),",
"BRAF",
"and",
"KRAS",
"mutation",
"occurred",
"with",
"similar",
"frequency",
"in",
"both",
"MPs",
"(40%",
"and",
"50%,",
"respectively)",
"and",
"SAs",
"(33%",
"and",
"27%,",
"respectively).",
"In",
"the",
"literature,",
"the",
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"mutation",
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"MP",
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"SA",
"has",
"ranged",
"from",
"36",
"to",
"100%",
"and",
"from",
"0%",
"to",
"60%,",
"respectively.12,16,39β42",
"These",
"findings",
"indicate",
"that",
"this",
"subset",
"of",
"colorectal",
"polyps",
"is",
"likely",
"to",
"be",
"heterogeneous",
"in",
"terms",
"of",
"its",
"molecular",
"origins.",
"These",
"polyps",
"were",
"therefore",
"reclassified",
"according",
"to",
"their",
"resemblance",
"to",
"HP",
"or",
"SSA",
"HP",
"mutation",
"microvesicular",
"β,",
"in",
"which",
"the",
"columnar",
"cells",
"contain",
"apical",
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"droplets",
"within",
"small",
"vesicles",
"while",
"goblet",
"cells",
"are",
"rendered",
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"mutation",
"occurs",
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"in",
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"variant",
" ",
"of",
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"By",
"contrast,",
"KRAS",
"mutation",
"occurs",
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"more",
"commonly",
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"the",
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"cell",
"variant",
"of",
"HP,",
"which",
"is",
"usually",
"small,",
"located",
"in",
"the",
"left",
"colon",
"or",
"rectum",
"and",
"deviates",
"minimally",
"from",
"normal",
"colorectal",
"mucosa",
"in",
"terms",
"of",
"differentiation",
"and",
"architecture.16,25",
"The",
"latter",
"were",
"under-represented",
"in",
"this",
"series",
"(details",
"not",
"shown)."
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] | Serrated polyps with dysplasia, i.e. MPs and SAs, together comprised only 2% of the overall consecutive series of 1250 polyps. While mutation of KRAS and BRAF was associated with conventional adenoma and SSA, respectively (see above), BRAF and KRAS mutation occurred with similar frequency in both MPs (40% and 50%, respectively) and SAs (33% and 27%, respectively). In the literature, the frequency of BRAF and KRAS mutation in MP or SA has ranged from 36 to 100% and from 0% to 60%, respectively.12,16,39β42 These findings indicate that this subset of colorectal polyps is likely to be heterogeneous in terms of its molecular origins. These polyps were therefore reclassified according to their resemblance to HP or SSA HP mutation microvesicular β, in which the columnar cells contain apical mucin droplets within small vesicles while goblet cells are rendered inconspicuous.25BRAF mutation occurs more frequently in the microvesicular variant of HP.16 By contrast, KRAS mutation occurs much more commonly in the goblet cell variant of HP, which is usually small, located in the left colon or rectum and deviates minimally from normal colorectal mucosa in terms of differentiation and architecture.16,25 The latter were under-represented in this series (details not shown). |
1334229-03-Methods-p01 | [
"Tumour",
"material",
"of",
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"cancer",
"patients",
"was",
"collected",
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"colorectal",
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"patients",
"were",
"localized",
"in",
"54",
"pathology",
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"samples",
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"samples,",
"737",
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"colon",
"women",
" ",
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"ages",
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] | Tumour material of colorectal cancer patients was collected after approval by the Ethical Review Board of Maastricht University, PALGA and the NCR. Tissue samples from 819 colorectal cancer patients were localized in 54 pathology laboratories throughout the Netherlands. Forty-four (5%) tumour tissue samples could not be retrieved from the pathology archives. Of 775 available tissue samples, 737 cecum through sigmoid colon colon women between the ages of 55 and 69 years at baseline. |
1619718-05-Discussion-p03 | [
"Concept",
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"βfusionβ",
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] | [
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] | Concept of βfusionβ pathways to crc |
2386495-05-Discussion-p02 | [
"The",
"fraction",
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"large",
"deletions",
"of",
"all",
"APC",
"mutations",
"identified",
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"the",
"Swedish",
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"was",
"9%,",
"which",
"is",
"higher",
"than",
"the",
"5%",
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" ",
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"number",
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"polyps,",
"comparably",
"high",
"age",
"at",
"diagnosis,",
"and",
"a",
"low",
"frequency",
"of",
"extracolonic",
"manifestations.",
"Whether",
"these",
"patients",
"really",
"are",
"affected",
"by",
"APC-associated",
"FAP",
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"be",
"called",
"into",
"question.",
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"attenuated",
"cases",
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"FAP",
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"subtle",
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"mosaic",
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">",
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" ",
"have",
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"al",
"[42],",
"in",
"which",
"the",
"internal",
"ATG",
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"codon",
"184",
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"an",
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"in",
"the",
"allele",
"carrying",
"a",
"truncating",
"mutation",
"upstream",
"of",
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"site",
"(Figure",
"1).",
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"would",
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"length,",
"thus",
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"large",
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"polyps,",
"duodenal",
"adenomas,",
"and",
"fundic",
"gland",
"polyps",
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"file",
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] | The fraction of large deletions of all APC mutations identified in the Swedish patients was 9%, which is higher than the 5% attenuated form of disease with a low number of polyps, comparably high age at diagnosis, and a low frequency of extracolonic manifestations. Whether these patients really are affected by APC-associated FAP can (of course) be called into question. However, among attenuated cases of FAP in these study we have found very subtle mutations such as the mosaic case as well as the c.70C > T mutation and splice-site mutations APC have been suggested by Heppner Goss et al [42], in which the internal ATG at codon 184 could be used as an alternative translation initiation codon in the allele carrying a truncating mutation upstream of this site (Figure 1). Such an alternative start of translation would supply the cell with an APC protein of almost full length, thus explaining the attenuated phenotype. Patient C159, with the most 3' localized mutation was a case of attenuated FAP (100β1000 polyps, 46 years of age at diagnosis). In family 1 (reduced expression of APC APC protein of almost full length, thus explaining the attenuated phenotype. Patient C159, with the most 3' localized mutation was a case of attenuated FAP (100β1000 polyps, 46 years of age at diagnosis). In family 1 (reduced expression of APC), patient C152 displayed a classical FAP phenotype including a large number of polyps, duodenal adenomas, and fundic gland polyps (Additional file 1). |
1619718-05-Discussion-p03 | [
"ACF,",
"Aberrant",
"crypt",
"foci",
"(hyperplastic",
"or",
"dysplastic);",
"HP,",
"hyperplastic",
"polyp;",
"SSA,",
"sessile",
"serrated",
"adenoma;",
"SA,",
"serrated",
"adenoma;",
"TA,",
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] | ACF, Aberrant crypt foci (hyperplastic or dysplastic); HP, hyperplastic polyp; SSA, sessile serrated adenoma; SA, serrated adenoma; TA, tubular adenoma. |
1373649-04-Results-and-discussion-p01 | [
"A",
"more",
"sensitive",
"approach",
"has",
"been",
"reported",
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"a",
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] | A more sensitive approach has been reported using a quasimonomorphic mononucleotide markers panel (that includes BAT-25 and BAT-26) without the need to match normal DNA[11]. |
1557864-03-Methods-p01 | [
"The",
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"design",
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"were",
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"The",
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"and",
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"are",
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"1.",
"Forty-six",
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] | The study design was approved by the medical ethical committee of the Erasmus MC Rotterdam, the Netherlands (MEC 02.949). Tissue of 75 ovarian cancer patients and four normal stromal ovarian tissues collected at the Erasmus MC in Rotterdam were included in this study. The patient and tumor characteristics are listed in Table 1. Forty-six patients received platinum-based chemotherapy of whom 34 responded to treatment defined as complete response, partial response, stable disease or no relapse within 6 months after chemotherapy, whereas eleven patients had progressive disease or a relapse within 6 months after chemotherapy. In one patient the response was not known. The response rate of 74% (34/46) is comparable with the response rate of 80% seen in the clinic. A more detailed description of the response definitions has been previously described by us [5]. The median age at the time of surgery was 52 years (range 27β83). |
1619718-03-Materials-and-methods-p02 | [
"BRAF",
"mutation",
"analysis",
"at",
"codon",
"600",
"(V600E;",
"formerly",
"V599E)",
"was",
"performed",
"by",
"a",
"real-time",
"PCR-based",
"allelic",
"discrimination",
"method",
"as",
"previously",
"described.29",
"Briefly,",
"real-time",
"PCR",
"was",
"performed",
"using",
"allele-specific",
"primers",
"designed",
"to",
"amplify",
"selectively",
"the",
"wild-type",
"(T1796)",
"and",
"mutant",
"(A1796)",
"BRAF",
"alleles.",
"The",
"primer",
"sequences",
"were",
"as",
"follows:",
"V,",
"5β²-GTGATTTTGGTCTAGCTACtGT;",
"E,",
"5β²-CGCGGCCGGCCGCGGCGGTGATTTTGGTCTAGCTACcGA;",
"AS,",
"5β²-TAGCCTCAATTCTTACCATCCAC.",
"PCR",
"amplification",
"and",
"melting",
"curve",
"analysis",
"were",
"performed",
"on",
"a",
"Rotor-gene",
"3000",
"(Corbett",
"Research,",
"NSW,",
"Australia).",
"Genomic",
"DNA",
"was",
"amplified",
"in",
"a",
"15-Β΅l",
"volume",
"containing",
"1",
"Γ",
"Platinum",
"SYBR",
"Green",
"qPCR",
"SuperMix-UDG",
"(Invitrogen,",
"Carlsbad,",
"CA,",
"USA),",
"forward",
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"V",
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"nm),",
"forward",
"primer",
"E",
"(900",
"nm)",
"and",
"reverse",
"primer",
"AS",
"(300",
"nm).",
"The",
"cycling",
"conditions",
"were",
"as",
"follows:",
"50Β°C",
"for",
"2",
"min,",
"95Β°C",
"for",
"2",
"min,",
"40",
"cycles",
"of",
"95Β°C",
"for",
"15",
"s",
"and",
"60Β°C",
"for",
"60",
"s.",
"After",
"amplification,",
"samples",
"were",
"subjected",
"to",
"a",
"temperature",
"ramp",
"from",
"60Β°C",
"to",
"99Β°C,",
"rising",
"1Β°C",
"each",
"step.",
"For",
"wild-type",
"samples,",
"single",
"peaks",
"were",
"observed",
"at",
"80Β°C",
"while",
"samples",
"containing",
"mutant",
"alleles",
"produced",
"single",
"peaks",
"at",
"85Β°C."
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] | BRAF mutation analysis at codon 600 (V600E; formerly V599E) was performed by a real-time PCR-based allelic discrimination method as previously described.29 Briefly, real-time PCR was performed using allele-specific primers designed to amplify selectively the wild-type (T1796) and mutant (A1796) BRAF alleles. The primer sequences were as follows: V, 5β²-GTGATTTTGGTCTAGCTACtGT; E, 5β²-CGCGGCCGGCCGCGGCGGTGATTTTGGTCTAGCTACcGA; AS, 5β²-TAGCCTCAATTCTTACCATCCAC. PCR amplification and melting curve analysis were performed on a Rotor-gene 3000 (Corbett Research, NSW, Australia). Genomic DNA was amplified in a 15-Β΅l volume containing 1 Γ Platinum SYBR Green qPCR SuperMix-UDG (Invitrogen, Carlsbad, CA, USA), forward primer V (300 nm), forward primer E (900 nm) and reverse primer AS (300 nm). The cycling conditions were as follows: 50Β°C for 2 min, 95Β°C for 2 min, 40 cycles of 95Β°C for 15 s and 60Β°C for 60 s. After amplification, samples were subjected to a temperature ramp from 60Β°C to 99Β°C, rising 1Β°C each step. For wild-type samples, single peaks were observed at 80Β°C while samples containing mutant alleles produced single peaks at 85Β°C. |
1360090-03-Results-p01 | [
"BRAF",
"mutations",
"showed",
"no",
"association",
"with",
"TP53",
"mutations",
"and",
"were",
"mutually",
"exclusive",
"with",
"the",
"presence",
"of",
"KRAS",
"mutations",
"(Table",
"2).",
"In",
"contrast,",
"BRAF",
"mutations",
"were",
"approximately",
"10-fold",
"more",
"frequent",
"in",
"MSI+",
"and",
"CIMP+",
"tumors",
"compared",
"to",
"tumors",
"without",
"these",
"phenotypes.",
"A",
"strong",
"association",
"was",
"also",
"seen",
"with",
"methylation",
"of",
"the",
"MLH1",
"gene",
"promoter",
"and",
"in",
"particular",
"with",
"methylation",
"of",
"its",
"proximal",
"region.",
"We",
"have",
"previously",
"examined",
"the",
"methylation",
"status",
"of",
"7",
"different",
"CpG",
"islands",
"in",
"this",
"CRC",
"series",
"[18].",
"The",
"mean",
"number",
"of",
"these",
"methylated",
"sites",
"was",
"3-fold",
"higher",
"in",
"tumors",
"with",
"BRAF",
"mutation",
"compared",
"to",
"those",
"without",
"(2.6",
"Β±",
"1.7",
"vs",
"0.8",
"Β±",
"1.0;",
"P",
"<",
"0.001).",
"Multivariate",
"analysis",
"revealed",
"that",
"MSI+",
"was",
"the",
"only",
"significant",
"independent",
"predictor",
"of",
"BRAF",
"mutation",
"(RR",
"=",
"6.3,",
"95%CI",
"[1.2β32.3];",
"P",
"=",
"0.028)",
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"model",
"that",
"included",
"CIMP+,",
"tumor",
"site,",
"histological",
"grade,",
"presence",
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] | BRAF mutations showed no association with TP53 mutations and were mutually exclusive with the presence of KRAS mutations (Table 2). In contrast, BRAF mutations were approximately 10-fold more frequent in MSI+ and CIMP+ tumors compared to tumors without these phenotypes. A strong association was also seen with methylation of the MLH1 gene promoter and in particular with methylation of its proximal region. We have previously examined the methylation status of 7 different CpG islands in this CRC series [18]. The mean number of these methylated sites was 3-fold higher in tumors with BRAF mutation compared to those without (2.6 Β± 1.7 vs 0.8 Β± 1.0; P < 0.001). Multivariate analysis revealed that MSI+ was the only significant independent predictor of BRAF mutation (RR = 6.3, 95%CI [1.2β32.3]; P = 0.028) in a model that included CIMP+, tumor site, histological grade, presence of infiltrating lymphocytes and mucinous appearance. |
2386495-04-Results-p02 | [
"A",
"case",
"of",
"APC",
"mosaicism"
] | [
0,
0,
0,
0,
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] | A case of APC mosaicism |
1601966-03-Results-p04 | [
"Up-regulation",
"of",
"mRNA",
"expression",
"in",
"human",
"chromosomal",
"region",
"8q11.23-q21.13",
"(patient",
"counts",
"with",
"coordinate",
"down-regulation).",
"Grayscale",
"plot",
"of",
"cross-comparison",
"of",
"down-regulation",
"patterns",
"across",
"patients",
"for",
"gene",
"pairs",
"in",
"a",
"particular",
"region.",
"Both,",
"horizontal",
"and",
"vertical",
"axes",
"comprise",
"the",
"same",
"genes",
"in",
"chromosomal",
"order.",
"In",
"each",
"square",
"total",
"counts",
"of",
"patients",
"with",
"consistent",
"down-regulation",
"in",
"two",
"genes",
"are",
"coded",
"by",
"different",
"shades",
"of",
"gray.",
"Dark",
"squared",
"regions",
"along",
"the",
"diagonal",
"indicate",
"coordinated",
"regulation",
"in",
"patient",
"subgroups.",
"View",
"in",
"conjunction",
"with",
"Figures",
"6",
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"7."
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] | Up-regulation of mRNA expression in human chromosomal region 8q11.23-q21.13 (patient counts with coordinate down-regulation). Grayscale plot of cross-comparison of down-regulation patterns across patients for gene pairs in a particular region. Both, horizontal and vertical axes comprise the same genes in chromosomal order. In each square total counts of patients with consistent down-regulation in two genes are coded by different shades of gray. Dark squared regions along the diagonal indicate coordinated regulation in patient subgroups. View in conjunction with Figures 6 and 7. |
1619718-01-Abstract-p01 | [
"Thirty-two",
"sessile",
"serrated",
"adenomas",
"(SSA),",
"10",
"mixed",
"polyps",
"(MP),",
"15",
"traditional",
"serrated",
"adenomas",
"(SA),",
"49",
"hyperplastic",
"polyps",
"(",
"HP",
"colorectal",
" ",
"polyps",
"with",
"the",
"molecular",
"and",
"morphological",
"features",
"of",
"serrated",
"polyps",
"and",
"adenomas:",
"concept",
"of",
"a",
"βfusionβ",
"pathway",
"to",
"colorectal",
"cancer"
] | [
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] | Thirty-two sessile serrated adenomas (SSA), 10 mixed polyps (MP), 15 traditional serrated adenomas (SA), 49 hyperplastic polyps ( HP colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a βfusionβ pathway to colorectal cancer |
1557864-05-Discussion-p03 | [
"The",
"relation",
"between",
"MMR",
"deficiency",
"and",
"platinum-drug",
"resistance",
"has",
"been",
"investigated",
"in",
"only",
"a",
"few",
"in",
"vivo",
"studies.",
"Similarly",
"to",
"our",
"result,",
"no",
"MSI",
"was",
"detected",
"by",
"Mesquita",
"et",
"al.",
"[18]",
"who",
"studied",
"34",
"ovarian",
"carcinomas",
"of",
"which",
"seven",
"34",
"did",
"not",
"respond",
" ",
"and",
"34",
"did",
"9%",
" ",
"and",
"8%,",
"respectively)",
"(Table",
"2).",
"We",
"hypothesize",
"that",
"mucinous",
"and",
"endometrioid",
"histology",
"might",
"be",
"prone",
"to",
"a",
"higher",
"MSI",
"frequency",
"since",
"sporadic",
"endometrial",
"carcinoma,",
"which",
"is",
"closely",
"related",
"to",
"endometrioid",
"ovarian",
"cancer,",
"has",
"a",
"MSI",
"frequency",
"of",
"20β30%",
"[49-51]",
"and",
"MSI",
"is",
"almost",
"universal",
"present",
"in",
"the",
"colorectal",
"tumors",
"of",
"the",
"hereditary",
"nonpolyposis",
"colon",
"cancer",
"(HNPCC)",
"syndrome",
"which",
"all",
"have",
"a",
"mucinous",
"histological",
"type.",
"Therefore,",
"the",
"different",
"histology's",
"of",
"the",
"ovarian",
"carcinomas",
"included",
"in",
"the",
"several",
"studies",
"seems",
"to",
"be",
"a",
"plausible",
"cause",
"for",
"the",
"wide",
"range",
"in",
"MSI",
"frequency",
"reported",
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] | The relation between MMR deficiency and platinum-drug resistance has been investigated in only a few in vivo studies. Similarly to our result, no MSI was detected by Mesquita et al. [18] who studied 34 ovarian carcinomas of which seven 34 did not respond and 34 did 9% and 8%, respectively) (Table 2). We hypothesize that mucinous and endometrioid histology might be prone to a higher MSI frequency since sporadic endometrial carcinoma, which is closely related to endometrioid ovarian cancer, has a MSI frequency of 20β30% [49-51] and MSI is almost universal present in the colorectal tumors of the hereditary nonpolyposis colon cancer (HNPCC) syndrome which all have a mucinous histological type. Therefore, the different histology's of the ovarian carcinomas included in the several studies seems to be a plausible cause for the wide range in MSI frequency reported in these studies. |
1266026-04-Results-p01 | [
"Ages",
"at",
"cancer",
"can",
"be",
"used",
"to",
"estimate",
"likely",
"numbers",
"of",
"oncogenic",
"mutations",
"required",
"before",
"transformation",
"[3-6,11].",
"Average",
"ages",
"for",
"sporadic",
"MSI+,",
"MSI-,",
"and",
"HNPCC",
"cancers",
"were",
"respectively",
"71.5,",
"67.5,",
"and",
"50.3",
"years",
"(Figure",
"1A).",
"For",
"HNPCC",
"cancers,",
"estimated",
"numbers",
"of",
"oncogenic",
"mutations",
"were",
"between",
"four",
"and",
"seven",
"(95%",
"credibility",
"interval),",
"with",
"the",
"most",
"likely",
"value",
"of",
"five",
"mutations",
"(Table",
"1).",
"For",
"MSI+",
"sporadic",
"cancers,",
"estimated",
"numbers",
"of",
"mutations",
"were",
"between",
"six",
"and",
"nine",
"(95%",
"credibility",
"interval)",
"with",
"more",
"likely",
"values",
"of",
"seven",
"or",
"eight",
"mutations.",
"The",
"most",
"likely",
"number",
"of",
"mutations",
"was",
"seven",
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] | Ages at cancer can be used to estimate likely numbers of oncogenic mutations required before transformation [3-6,11]. Average ages for sporadic MSI+, MSI-, and HNPCC cancers were respectively 71.5, 67.5, and 50.3 years (Figure 1A). For HNPCC cancers, estimated numbers of oncogenic mutations were between four and seven (95% credibility interval), with the most likely value of five mutations (Table 1). For MSI+ sporadic cancers, estimated numbers of mutations were between six and nine (95% credibility interval) with more likely values of seven or eight mutations. The most likely number of mutations was seven for sporadic MSI- cancers. |
1601966-03-Results-p03 | [
"Statistics",
"on",
"expression",
"imbalances",
"across",
"human",
"chromosomes."
] | [
0,
0,
0,
0,
0,
0,
0
] | Statistics on expression imbalances across human chromosomes. |
1619718-05-Discussion-p03 | [
"Concept",
"of",
"βfusionβ",
"pathways",
"to",
"crc"
] | [
0,
0,
0,
0,
0,
0
] | Concept of βfusionβ pathways to crc |
1557864-01-Abstract-p01 | [
"Conclusion"
] | [
0
] | Conclusion |
3034663-02-Background-p01 | [
"Lynch",
"syndrome",
"(MIM#",
"120435)",
"(LS)",
"is",
"an",
"autosomal",
"dominant",
"inherited",
"cancer",
"syndrome",
"characterized",
"by",
"early",
"onset",
"colorectal",
"early",
"onset",
" ",
"colorectal",
"cancer",
"missense",
"substitutions",
"small",
"in-frame",
"deletions",
".",
"The",
"human",
"gene",
"pool",
"harbours",
"a",
"vast",
"number",
"of",
"rare",
"missense",
"substitutions,",
"70%",
"of",
"which",
"are",
"at",
"least",
"mildly",
"deleterious",
"[2].",
"Integration",
"of",
"various",
"lines",
"of",
"evidence",
"may",
"help",
"to",
"classify",
"UVs.",
"Information",
"on:",
"1)",
"frequencies",
"in",
"cases",
"and",
"controls,",
"2)",
"co-occurrence",
"(in",
"trans)",
"with",
"deleterious",
"mutations,",
"3)",
"co-segregation",
"with",
"disease",
"in",
"pedigrees,",
"4)",
"pathological",
"factors,",
"5)",
"amino",
"acid",
"polarity",
"or",
"size,",
"6)",
"evolutionary",
"conservation",
"of",
"the",
"residue,",
"7)",
"splice",
"predictions",
"and",
"8)",
"in",
"vitro",
"and/or",
"in",
"vivo",
"functional",
"assays",
"may",
"enable",
"UVs",
"to",
"be",
"classified",
"as",
"pathogenic",
"or",
"non-pathogenic",
"[3]."
] | [
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19,
20,
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] | Lynch syndrome (MIM# 120435) (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset colorectal early onset colorectal cancer missense substitutions small in-frame deletions . The human gene pool harbours a vast number of rare missense substitutions, 70% of which are at least mildly deleterious [2]. Integration of various lines of evidence may help to classify UVs. Information on: 1) frequencies in cases and controls, 2) co-occurrence (in trans) with deleterious mutations, 3) co-segregation with disease in pedigrees, 4) pathological factors, 5) amino acid polarity or size, 6) evolutionary conservation of the residue, 7) splice predictions and 8) in vitro and/or in vivo functional assays may enable UVs to be classified as pathogenic or non-pathogenic [3]. |
1619718-04-Results-p03 | [
"Sixty-two",
"TAs,",
"22",
"TVAs/VAs,",
"15",
"SAs",
"and",
"10",
"MPs",
"were",
"immunostained",
"for",
"p53.",
"Weak",
"expression",
"of",
"nuclear",
"p53",
"occurred",
"frequently",
"within",
"the",
"proliferative",
"compartment",
"in",
"all",
"types",
"of",
"polyps",
"and",
"was",
"ignored.",
"Aberrant",
"p53",
"expression",
"was",
"observed",
"in",
"only",
"four",
"polyps:",
"one",
"TA,",
"one",
"MP",
"(Figure",
"1B)",
"and",
"two",
"SAs",
"(Figure",
"2).",
"Overall,",
"only",
"1/84",
"(1%)",
"conventional",
"adenomas",
"showed",
"aberrant",
"expression",
"of",
"p53",
"compared",
"with",
"3/25",
"(12%)",
"serrated",
"polyps",
"with",
"dysplasia",
"(P",
"<",
"0.04).",
"In",
"the",
"latter,",
"aberrant",
"p53",
"expression",
"coincided",
"with",
"high-grade",
"dysplasia",
"and",
"reduced",
"or",
"complete",
"loss",
"of",
"expression",
"of",
"MGMT",
"(Figures",
"1B",
"and",
"2).",
"The",
"TA",
"with",
"aberrant",
"p53",
"expression",
"had",
"normal",
"expression",
"of",
"MGMT."
] | [
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] | Sixty-two TAs, 22 TVAs/VAs, 15 SAs and 10 MPs were immunostained for p53. Weak expression of nuclear p53 occurred frequently within the proliferative compartment in all types of polyps and was ignored. Aberrant p53 expression was observed in only four polyps: one TA, one MP (Figure 1B) and two SAs (Figure 2). Overall, only 1/84 (1%) conventional adenomas showed aberrant expression of p53 compared with 3/25 (12%) serrated polyps with dysplasia (P < 0.04). In the latter, aberrant p53 expression coincided with high-grade dysplasia and reduced or complete loss of expression of MGMT (Figures 1B and 2). The TA with aberrant p53 expression had normal expression of MGMT. |
2275286-05-Discussion-p01 | [
"At",
"present,",
"a",
"number",
"of",
"publications",
"have",
"studied",
"the",
"value",
"of",
"the",
"revised",
"Bethesda",
"criteria",
"and",
"the",
"relevant",
"diagnostic",
"procedures",
"[13,14].",
"However,",
"there",
"has",
"not",
"been",
"any",
"systematic",
"report",
"on",
"germline",
"mutations",
"of",
"MMR",
"genes",
"in",
"the",
"Chinese",
"population.",
"Moreover,",
"we",
"found",
"that",
"research",
"from",
"some",
"countries",
"have",
"results",
"that,",
"if",
"applied",
"to",
"the",
"NCI",
"recommendations,",
"may",
"have",
"resulted",
"in",
"a",
"missed",
"HNPCC",
"family",
"or",
"low",
"pick-up",
"rate",
"of",
"HNPCC.",
"In",
"a",
"study",
"by",
"Pinol",
"et",
"al.",
"from",
"Spain",
"[13],",
"287",
"out",
"of",
"1222",
"patients",
"(23.5%)",
"complied",
"with",
"the",
"revised",
"Bethesda",
"standard.",
"Ninety-one",
"patients",
"(7.4%)",
"were",
"MSI",
"carriers,",
"but",
"only",
"11",
"patients",
"(0.9%)",
"had",
"germline",
"mutations",
"of",
"MSH2",
"or",
"MLH1.",
"This",
"means",
"that",
"among",
"this",
"group,",
"only",
"0.9%",
"of",
"patients",
"could",
"be",
"diagnosed",
"as",
"HNPCC.",
"In",
"a",
"study",
"by",
"Yearsley",
"et",
"al.",
"[14],",
"out",
"of",
"482",
"US",
"patients",
"with",
"colorectal",
"cancers,",
"87",
"patients",
"(18%)",
"were",
"MSI",
"carriers",
"and",
"only",
"12",
"cases",
"(2.5%)",
"had",
"MMR",
"gene",
"germline",
"mutations.",
"These",
"results",
"may",
"be",
"explained",
"by",
"different",
"case",
"selections",
"and",
"sensitivity",
"of",
"the",
"tests",
"used.",
"On",
"the",
"other",
"hand,",
"in",
"their",
"study",
"of",
"HNPCC",
"related",
"tumors",
"in",
"young",
"patients",
"(<50",
"years",
"old),",
"Niessen",
"et",
"al.",
"[15]",
"found",
"that",
"the",
"rate",
"of",
"MSH2,",
"MSH6",
"and",
"MLH1",
"germline",
"mutations",
"in",
"MSI",
"carriers",
"was",
"82%.",
"In",
"our",
"146",
"patients",
"with",
"colorectal",
"cancers,",
"34",
"patients",
"(23.3%)",
"had",
"MSI",
"colorectal",
"cancer.",
"This",
"is",
"comparable",
"to",
"the",
"studies",
"by",
"Pinol",
"et",
"al.",
"[13]",
"and",
"Yearsley",
"et",
"al.",
"[16].",
"Wong",
"et",
"al.",
"[17]",
"showed",
"that",
"in",
"the",
"case",
"of",
"sporadic",
"endometrial",
"carcinoma,",
"MSI",
"endometrial",
"carcinoma",
"accounted",
"for",
"26%",
"of",
"patients.",
"Our",
"results",
"showed",
"that",
"there",
"were",
"15",
"(10.3%)",
"CRCs",
"with",
"MSI-L",
"and",
"19",
"(13.0%)",
"CRCs",
"with",
"MSL-H,",
"respectively.",
"Lamberti",
"et",
"al.",
"[18]",
"reported",
"that",
"MSI-L",
"and",
"MSI-H",
"accounted",
"for",
"6%",
"and",
"17%,",
"respectively,",
"of",
"German",
"patients.",
"These",
"results",
"are",
"similar",
"to",
"ours.",
"Unexpectedly,",
"in",
"the",
"present",
"study,",
"the",
"age",
"of",
"patients",
"with",
"MSS",
"colorectal",
"cancers",
"(60",
"yrs)",
"was",
"similar",
"to",
"the",
"age",
"of",
"patients",
"with",
"MSI-H",
"(61",
"yrs).",
"In",
"contrast,",
"the",
"average",
"age",
"of",
"patients",
"with",
"MSI-L",
"colorectal",
"cancer",
"was",
"71,",
"which",
"was",
"quite",
"different",
"from",
"the",
"reports",
"of",
"other",
"research",
"groups",
"[13,15,18].",
"In",
"a",
"study",
"of",
"1263",
"patients",
"with",
"colorectal",
"cancers,",
"Benatti",
"et",
"al.",
"[19]",
"found",
"that",
"those",
"who",
"were",
"MSI",
"carriers",
"tended",
"to",
"have",
"mucinous",
"and",
"right",
"colonic",
"tumours.",
"Noda",
"et",
"al.",
"[20]",
"also",
"found",
"that",
"MSI",
"carriers",
"have",
"more",
"right",
"colonic",
"tumors.",
"However,",
"in",
"our",
"study,",
"tumors",
"in",
"the",
"MSI",
"group",
"were",
"most",
"commonly",
"located",
"at",
"the",
"rectum,",
"and",
"mucinous",
"carcinoma",
"was",
"not",
"the",
"most",
"common",
"pathological",
"type,",
"as",
"it",
"only",
"accounted",
"for",
"29%.",
"Interestingly,",
"patients",
"in",
"our",
"MSI-L",
"group",
"were",
"older",
"than",
"the",
"MSS",
"group.",
"The",
"reason",
"for",
"these",
"findings",
"is",
"uncertain.",
"Bettstetter",
"et",
"al.",
"[20]",
"reported",
"that",
"the",
"average",
"age",
"of",
"MSI",
"CRCs",
"with",
"MLH1",
"negative",
"staining",
"was",
"80",
"yrs,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Most",
"of",
"these",
"MSI",
"CRCs",
"were",
"caused",
"by",
"MLH1",
"promoter",
"hypermethylation.",
"In",
"our",
"group,",
"out",
"of",
"34",
"MSI",
"CRCs,",
"19",
"CRCs",
"(55.9%)",
"were",
"hypermethylated",
"at",
"the",
"MLH1",
"promoter,",
"which",
"accounted",
"for",
"73.7%",
"of",
"MSI-H",
" ",
"CRCs",
"and",
"33.3%",
"of",
"MSI",
"CRCs.",
"Anacleto",
"et",
"al.",
"[21]",
"reported",
"that",
"8",
"out",
"of",
"15",
"MSI",
"CRCs",
"had",
"MLH1",
"promoter",
"hypermethylation,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Kim",
"et",
"al.",
"[10]",
"found",
"that",
"in",
"MSI-H",
"gastric",
"cancers,",
"the",
"MLH1",
"hypermethylation",
"occurred",
"in",
"89%",
"of",
"patients.",
"Bettstetter",
"et",
"al.",
"[20]",
"showed",
"that",
"all",
"sporadic",
"MSI-H",
"MSI-H",
"MSI",
"80",
"yrs",
",",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Most",
"of",
"these",
"MSI",
"CRCs",
"were",
"caused",
"by",
"MLH1",
"promoter",
"hypermethylation",
".",
"In",
"our",
"group,",
"out",
"of",
"34",
"MSI",
"CRCs",
"MSI",
" ",
"CRCs,",
"19",
"CRCs",
"15",
"HNPCC",
"related",
" ",
"tumors",
"in",
"young",
"patients",
"(<50",
"years",
"old),",
"Niessen",
"et",
"al.",
"[15]",
"found",
"that",
"the",
"rate",
"of",
"MSH2,",
"MSH6",
"and",
"MLH1",
"germline",
"mutations",
"in",
"MSI",
"carriers",
"was",
"82%.",
"In",
"our",
"146",
"patients",
"with",
"colorectal",
"cancers,",
"34",
"patients",
"(23.3%)",
"had",
"MSI",
"colorectal",
"cancer.",
"This",
"is",
"comparable",
"to",
"the",
"studies",
"by",
"Pinol",
"et",
"al.",
"[13]",
"and",
"Yearsley",
"et",
"al.",
"[16].",
"Wong",
"et",
"al.",
"[17]",
"showed",
"that",
"in",
"the",
"case",
"of",
"sporadic",
"endometrial",
"carcinoma,",
"MSI",
"endometrial",
"carcinoma",
"accounted",
"for",
"26%",
"of",
"patients.",
"Our",
"results",
"showed",
"that",
"there",
"were",
"15",
"(10.3%)",
"CRCs",
"with",
"MSI-L",
"and",
"19",
"(13.0%)",
"CRCs",
"with",
"MSL-H,",
"respectively.",
"Lamberti",
"et",
"al.",
"[18]",
"reported",
"that",
"MSI-L",
"and",
"MSI-H",
"accounted",
"for",
"6%",
"and",
"17%,",
"respectively,",
"of",
"German",
"patients.",
"These",
"results",
"are",
"similar",
"to",
"ours.",
"Unexpectedly,",
"in",
"the",
"present",
"study,",
"the",
"age",
"of",
"patients",
"with",
"MSS",
"colorectal",
"cancers",
"(60",
"yrs)",
"was",
"similar",
"to",
"the",
"age",
"of",
"patients",
"with",
"MSI-H",
"(61",
"yrs).",
"In",
"contrast,",
"the",
"average",
"age",
"of",
"patients",
"with",
"MSI-L",
"colorectal",
"cancer",
"was",
"71,",
"which",
"was",
"quite",
"different",
"from",
"the",
"reports",
"of",
"other",
"research",
"groups",
"[13,15,18].",
"In",
"a",
"study",
"of",
"1263",
"patients",
"with",
"colorectal",
"cancers,",
"Benatti",
"et",
"al.",
"[19]",
"found",
"that",
"those",
"who",
"were",
"MSI",
"carriers",
"tended",
"to",
"have",
"mucinous",
"and",
"right",
"colonic",
"tumours.",
"Noda",
"et",
"al.",
"[20]",
"also",
"found",
"that",
"MSI",
"carriers",
"have",
"more",
"right",
"colonic",
"tumors.",
"However,",
"in",
"our",
"study,",
"tumors",
"in",
"the",
"MSI",
"group",
"were",
"most",
"commonly",
"located",
"at",
"the",
"rectum,",
"and",
"mucinous",
"carcinoma",
"was",
"not",
"the",
"most",
"common",
"pathological",
"type,",
"as",
"it",
"only",
"accounted",
"for",
"29%.",
"Interestingly,",
"patients",
"in",
"our",
"MSI-L",
"group",
"were",
"older",
"than",
"the",
"MSS",
"group.",
"The",
"reason",
"for",
"these",
"findings",
"is",
"uncertain.",
"Bettstetter",
"et",
"al.",
"[20]",
"reported",
"that",
"the",
"average",
"age",
"of",
"MSI",
"CRCs",
"with",
"MLH1",
"negative",
"staining",
"was",
"80",
"yrs,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Most",
"of",
"these",
"MSI",
"CRCs",
"were",
"caused",
"by",
"MLH1",
"promoter",
"hypermethylation.",
"In",
"our",
"group,",
"out",
"of",
"34",
"MSI",
"CRCs,",
"19",
"CRCs",
"(55.9%)",
"were",
"hypermethylated",
"at",
"the",
"MLH1",
"promoter",
",",
"which",
"accounted",
"for",
"73.7%",
"of",
"MSI-H",
"CRCs",
"and",
"33.3%",
"of",
"MSI",
"CRCs.",
"Anacleto",
"et",
"al.",
"[21]",
"reported",
"that",
"8",
"out",
"of",
"15",
"MSI",
"CRCs",
"had",
"MLH1",
"promoter",
"hypermethylation,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Kim",
"et",
"al.",
"[10]",
"found",
"that",
"in",
"MSI-H",
"gastric",
"cancers,",
"the",
"MLH1",
"hypermethylation",
"occurred",
"in",
"89%",
"of",
"patients.",
"Bettstetter",
"et",
"al.",
"[20]",
"showed",
"that",
"all",
"sporadic",
"MSI-H",
"CRCs",
"were",
"hypermethylated",
"at",
"the",
"MLH1",
"promoter.",
"These",
"results",
"were",
"similar",
"to",
"ours.",
"Fourteen",
"out",
"of",
"16",
"MLH1",
"negatively",
"staining",
"CRCs",
"were",
"hypermethylated",
"at",
"the",
"MLH1promoter.",
"Mutation",
"analysis",
"revealed",
"that",
"8",
"patients",
"(23.5%)",
"had",
"MMR",
"gene",
"germline",
"mutations",
"out",
"of",
"34",
"MSI",
"patients.",
"Five",
"patients",
"had",
"MSH2",
"mutations",
"and",
"3",
"had",
"MSH6",
"mutations,",
"while",
"no",
"MLH1",
"mutation",
"was",
"found.",
"There",
"were",
"2",
"82%",
".",
"In",
"our",
"146",
"patients",
"with",
"colorectal",
"cancers,",
"34",
"patients",
"(23.3%)",
"had",
"MSI",
"colorectal",
"cancer.",
"This",
"is",
"comparable",
"to",
"the",
"studies",
"by",
"Pinol",
"et",
"al.",
"[13]",
"and",
"Yearsley",
"et",
"al.",
"[16].",
"Wong",
"et",
"al.",
"[17]",
"showed",
"that",
"in",
"the",
"case",
"of",
"sporadic",
"endometrial",
"carcinoma,",
"MSI",
"endometrial",
"carcinoma",
"accounted",
"for",
"26%",
"of",
"patients.",
"Our",
"results",
"showed",
"that",
"there",
"were",
"15",
"(10.3%)",
"CRCs",
"with",
"MSI-L",
"and",
"19",
"(13.0%)",
"CRCs",
"with",
"MSL-H,",
"respectively.",
"Lamberti",
"et",
"al.",
"[18]",
"reported",
"that",
"MSI-L",
"and",
"MSI-H",
"accounted",
"for",
"6%",
"and",
"17%,",
"respectively,",
"of",
"German",
"patients.",
"These",
"results",
"are",
"similar",
"to",
"ours.",
"Unexpectedly,",
"in",
"the",
"present",
"study,",
"the",
"age",
"of",
"patients",
"with",
"MSS",
"colorectal",
"cancers",
"(60",
"yrs)",
"was",
"similar",
"to",
"the",
"age",
"of",
"patients",
"with",
"MSI-H",
"(61",
"yrs).",
"In",
"contrast,",
"the",
"average",
"age",
"of",
"patients",
"with",
"MSI-L",
"colorectal",
"cancer",
"was",
"71,",
"which",
"was",
"quite",
"different",
"from",
"the",
"reports",
"of",
"other",
"research",
"groups",
"[13,15,18].",
"In",
"a",
"study",
"of",
"1263",
" ",
"patients",
"with",
"colorectal",
"cancers,",
"Benatti",
"et",
"al.",
"[19]",
"found",
"that",
"those",
"who",
"were",
"MSI",
"carriers",
"tended",
"to",
"have",
"mucinous",
"and",
"right",
"colonic",
"tumours.",
"Noda",
"et",
"al.",
"[20]",
"also",
"found",
"that",
"MSI",
"carriers",
"have",
"more",
"right",
"colonic",
"tumors.",
"However,",
"in",
"our",
"study,",
"tumors",
"in",
"the",
"MSI",
"group",
"were",
"most",
"commonly",
"located",
"at",
"the",
"rectum,",
"and",
"mucinous",
"carcinoma",
"was",
"not",
"the",
"most",
"common",
"pathological",
"type,",
"as",
"it",
"only",
"accounted",
"for",
"29%.",
"Interestingly,",
"patients",
"in",
"our",
"MSI-L",
"group",
"were",
"older",
"than",
"the",
"MSS",
"group.",
"The",
"reason",
"for",
"these",
"findings",
"is",
"uncertain.",
"Bettstetter",
"et",
"al.",
"[20]",
"reported",
"that",
"the",
"average",
"age",
"of",
"MSI",
"CRCs",
"with",
"MLH1",
"negative",
"staining",
"was",
"80",
"yrs,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Most",
"of",
"these",
"MSI",
"CRCs",
"were",
"caused",
"by",
"MLH1",
"promoter",
"hypermethylation.",
"In",
"our",
"group,",
"out",
"of",
"34",
"MSI",
"CRCs,",
"19",
"CRCs",
"(55.9%)",
"were",
"hypermethylated",
"at",
"the",
"MLH1",
"promoter,",
"which",
"accounted",
"for",
"73.7%",
"of",
"MSI-H",
"CRCs",
"26%",
" ",
"of",
"patients.",
"Our",
"results",
"showed",
"that",
"there",
"were",
"15",
"(10.3%)",
"CRCs",
"with",
"MSI-L",
"and",
"19",
"(13.0%)",
"CRCs",
"with",
"MSL-H,",
"respectively.",
"Lamberti",
"et",
"al.",
"[18]",
"reported",
"that",
"MSI-L",
"and",
"MSI-H",
"accounted",
"for",
"6%",
"and",
"17%,",
"respectively,",
"of",
"German",
"patients.",
"These",
"results",
"are",
"similar",
"to",
"ours.",
"Unexpectedly,",
"in",
"the",
"present",
"study,",
"the",
"age",
"of",
"patients",
"with",
"MSS",
"colorectal",
"cancers",
"(60",
"yrs)",
"was",
"similar",
"to",
"the",
"age",
"of",
"patients",
"with",
"MSI-H",
"(61",
"yrs).",
"In",
"contrast,",
"the",
"average",
"age",
"of",
"patients",
"with",
"MSI-L",
"colorectal",
"cancer",
"was",
"71,",
"which",
"was",
"quite",
"different",
"from",
"the",
"reports",
"of",
"other",
"research",
"groups",
"[13,15,18].",
"In",
"a",
"study",
"of",
"1263",
"patients",
"with",
"colorectal",
"cancers,",
"Benatti",
"et",
"al.",
"[19]",
"found",
"that",
"those",
"who",
"were",
"MSI",
"carriers",
"tended",
"to",
"have",
"mucinous",
"and",
"right",
"colonic",
"tumours.",
"Noda",
"et",
"al.",
"[20]",
"also",
"found",
"that",
"MSI",
"carriers",
"have",
"more",
"right",
"colonic",
"tumors.",
"However,",
"in",
"our",
"study,",
"tumors",
"in",
"the",
"MSI",
"group",
"were",
"most",
"commonly",
"located",
"at",
"the",
"rectum,",
"and",
"mucinous",
"carcinoma",
"was",
"not",
"the",
"most",
"common",
"pathological",
"type,",
"as",
"it",
"only",
"accounted",
"for",
"29%.",
"Interestingly,",
"patients",
"in",
"our",
"MSI-L",
"group",
"were",
"older",
"than",
"the",
"MSS",
"group.",
"The",
"reason",
"for",
"these",
"findings",
"is",
"uncertain.",
"Bettstetter",
"et",
"al.",
"[20]",
"reported",
"that",
"the",
"average",
"age",
"of",
"MSI",
"CRCs",
"with",
"MLH1",
"negative",
"staining",
"was",
"80",
"yrs,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Most",
"of",
"these",
"MSI",
"CRCs",
"were",
"caused",
"by",
"MLH1",
"promoter",
"hypermethylation.",
"In",
"our",
"group,",
"out",
"of",
"34",
"MSI",
"CRCs,",
"19",
"CRCs",
" ",
"(55.9%)",
"were",
"hypermethylated",
"at",
"the",
"MLH1",
"promoter,",
"which",
"accounted",
"for",
"73.7%",
"of",
"MSI-H",
"CRCs",
"and",
"33.3%",
"of",
"MSI",
"CRCs.",
"Anacleto",
"et",
"al.",
"[21]",
"reported",
"that",
"8",
"out",
"of",
"15",
"MSI",
"CRCs",
"had",
"MLH1",
"promoter",
"hypermethylation,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Kim",
"et",
"al.",
"[10]",
"found",
"that",
"in",
"MSI-H",
"gastric",
"cancers,",
"the",
"MLH1",
"hypermethylation",
"occurred",
"in",
"89%",
"of",
"patients.",
"Bettstetter",
"et",
"al.",
"[20]",
"showed",
"that",
"all",
"sporadic",
"MSI-H",
"CRCs",
"were",
"hypermethylated",
"at",
"the",
"MLH1",
"promoter.",
"These",
"results",
"were",
"similar",
"to",
"ours.",
"Fourteen",
"out",
"of",
"16",
"MLH1",
"negatively",
"staining",
"CRCs",
"were",
"hypermethylated",
"at",
"the",
"MLH1promoter.",
"Mutation",
"analysis",
"revealed",
"that",
"8",
"patients",
"(23.5%)",
"had",
"MMR",
"gene",
"germline",
"mutations",
"out",
"of",
"34",
"MSI",
"patients.",
"Five",
"patients",
"had",
"MSH2",
"mutations",
"and",
"3",
"had",
"MSH6",
"mutations,",
"while",
"no",
"MLH1",
"mutation",
"was",
"found.",
"There",
"were",
"2",
"and",
"6",
"patients",
"who",
"had",
"mutations",
"in",
"MSH2",
"and",
"MSH6",
"in",
"the",
"MSI-L",
"and",
"MSI-H",
"groups,",
"respectively.",
"Yearsley",
"et",
"al.",
"[15],",
"in",
"their",
"study",
"of",
"87",
"patients",
"with",
"MSI",
"colorectal",
"cancers",
"CRCs",
" ",
"with",
"MSI-L",
"and",
"19",
"(13.0%)",
"CRCs",
"with",
"MSL-H,",
"respectively.",
"Lamberti",
"et",
"al.",
"[18]",
"reported",
"that",
"MSI-L",
"and",
"MSI-H",
"accounted",
"for",
"6%",
"and",
"17%,",
"respectively,",
"of",
"German",
"patients.",
"These",
"results",
"are",
"similar",
"to",
"ours.",
"Unexpectedly,",
"in",
"the",
"present",
"study,",
"the",
"age",
"of",
"patients",
"with",
"MSS",
"colorectal",
"cancers",
"(60",
"yrs)",
"was",
"similar",
"to",
"the",
"age",
"of",
"patients",
"with",
"MSI-H",
"(61",
"yrs).",
"In",
"contrast,",
"the",
"average",
"age",
"of",
"patients",
"with",
"MSI-L",
"colorectal",
"cancer",
"colorectal",
"cancer",
" ",
"was",
"71,",
"which",
"was",
"quite",
"different",
"from",
"the",
"reports",
"of",
"other",
"research",
"groups",
"[13,15,18].",
"In",
"a",
"study",
"of",
"1263",
"patients",
"with",
"colorectal",
"cancers,",
"Benatti",
"et",
"al.",
"[19]",
"found",
"that",
"those",
"who",
"were",
"MSI",
"carriers",
"tended",
"to",
"have",
"mucinous",
"and",
"right",
"colonic",
"tumours.",
"Noda",
"et",
"al.",
"[20]",
"also",
"found",
"that",
"MSI",
"carriers",
"have",
"more",
"right",
"colonic",
"tumors.",
"However,",
"in",
"our",
"study,",
"tumors",
"in",
"the",
"MSI",
"group",
"were",
"most",
"commonly",
"located",
"at",
"the",
"rectum,",
"and",
"mucinous",
"carcinoma",
"was",
"not",
"the",
"most",
"common",
"pathological",
"type,",
"as",
"it",
"only",
"accounted",
"for",
"29%.",
"Interestingly,",
"patients",
"in",
"our",
"MSI-L",
"group",
"were",
"older",
"than",
"the",
"MSS",
"group.",
"The",
"reason",
"for",
"these",
"findings",
"is",
"uncertain.",
"Bettstetter",
"et",
"al.",
"[20]",
"reported",
"that",
"the",
"average",
"age",
"of",
"MSI",
"CRCs",
"with",
"MLH1",
"negative",
"staining",
"was",
"80",
"yrs,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Most",
"of",
"these",
"MSI",
"CRCs",
"were",
"caused",
"by",
"MLH1",
"promoter",
"hypermethylation.",
"In",
"our",
"group,",
"out",
"of",
"34",
"MSI",
"CRCs",
"CRCs",
"17%",
",",
"respectively,",
"of",
"German",
"patients.",
"These",
"results",
"are",
"similar",
"to",
"ours.",
"Unexpectedly,",
"in",
"the",
"present",
"study,",
"the",
"age",
"of",
"patients",
"with",
"MSS",
"colorectal",
"cancers",
"(60",
"yrs)",
"was",
"similar",
"to",
"the",
"age",
"of",
"patients",
"with",
"MSI-H",
"(61",
"yrs).",
"In",
"contrast,",
"the",
"average",
"age",
"of",
"patients",
"with",
"MSI-L",
"colorectal",
"cancer",
"was",
"71,",
"which",
"was",
"quite",
"different",
"from",
"the",
"reports",
"of",
"other",
"research",
"groups",
"[13,15,18].",
"In",
"a",
"study",
"of",
"1263",
"patients",
"with",
"colorectal",
"cancers,",
"Benatti",
"et",
"al.",
"[19]",
"found",
"that",
"those",
"who",
"were",
"MSI",
"carriers",
"tended",
"to",
"have",
"mucinous",
"and",
"right",
"colonic",
"tumours.",
"Noda",
"et",
"al.",
"[20]",
"also",
"found",
"that",
"MSI",
"carriers",
"have",
"more",
"right",
"colonic",
"tumors.",
"However,",
"in",
"our",
"study,",
"tumors",
"in",
"the",
"MSI",
"group",
"were",
"most",
"commonly",
"located",
"at",
"the",
"rectum,",
"and",
"mucinous",
"carcinoma",
"was",
"not",
"the",
"most",
"common",
"pathological",
"type,",
"as",
"it",
"only",
"accounted",
"for",
"29%.",
"Interestingly,",
"patients",
"in",
"our",
"MSI-L",
"group",
"were",
"older",
"than",
"the",
"MSS",
"group.",
"The",
"reason",
"for",
"these",
"findings",
"is",
"uncertain.",
"Bettstetter",
"et",
"al.",
"[20]",
"reported",
"that",
"the",
"average",
"age",
"of",
"MSI",
"CRCs",
"CRCs",
" ",
"with",
"MSL-H,",
"respectively.",
"Lamberti",
"et",
"al.",
"[18]",
"reported",
"that",
"MSI-L",
"and",
"MSI-H",
"accounted",
"for",
"6%",
"and",
"17%,",
"respectively,",
"of",
"German",
"patients.",
"These",
"results",
"are",
"similar",
"to",
"ours.",
"Unexpectedly,",
"in",
"the",
"present",
"study,",
"the",
"age",
"of",
"patients",
"with",
"MSS",
"colorectal",
"cancers",
"(60",
"yrs)",
"was",
"similar",
"to",
"the",
"age",
"of",
"patients",
"with",
"MSI-H",
"(61",
"yrs).",
"In",
"contrast,",
"the",
"average",
"age",
"of",
"patients",
"with",
"MSI-L",
"colorectal",
"cancer",
"was",
"71,",
"which",
"was",
"quite",
"different",
"from",
"the",
"reports",
"of",
"other",
"research",
"groups",
"[13,15,18].",
"In",
"a",
"study",
"of",
"1263",
"patients",
"with",
"colorectal",
"cancers,",
"Benatti",
"et",
"al.",
"[19]",
"found",
"that",
"those",
"who",
"were",
"MSI",
"carriers",
"tended",
"to",
"have",
"mucinous",
"and",
"right",
"colonic",
"tumours.",
"Noda",
"et",
"al.",
"[20]",
"also",
"found",
"that",
"MSI",
"carriers",
"have",
"more",
"right",
"colonic",
"tumors.",
"However,",
"in",
"our",
"study,",
"tumors",
"in",
"the",
"MSI",
"group",
"were",
"most",
"commonly",
"located",
"at",
"the",
"rectum,",
"and",
"mucinous",
"rectum",
"MSI",
" ",
"group",
"were",
"most",
"commonly",
"located",
"at",
"the",
"rectum,",
"and",
"mucinous",
"carcinoma",
"was",
"not",
"the",
"most",
"common",
"pathological",
"type,",
"as",
"it",
"only",
"accounted",
"for",
"29%.",
"Interestingly,",
"patients",
"in",
"our",
"MSI-L",
"group",
"were",
"older",
"than",
"the",
"MSS",
"group.",
"The",
"reason",
"for",
"these",
"findings",
"is",
"uncertain.",
"Bettstetter",
"et",
"al.",
"[20]",
"reported",
"that",
"the",
"average",
"age",
"of",
"MSI",
"CRCs",
"with",
"MLH1",
"negative",
"staining",
"was",
"80",
"yrs,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Most",
"of",
"these",
"MSI",
"CRCs",
"were",
"caused",
"by",
"MLH1",
"promoter",
"hypermethylation.",
"In",
"our",
"group,",
"out",
"of",
"34",
"MSI",
"CRCs,",
"19",
"CRCs",
"(55.9%)",
"were",
"hypermethylated",
"at",
"the",
"MLH1",
"promoter,",
"which",
"accounted",
"for",
"73.7%",
"of",
"MSI-H",
"CRCs",
"and",
"33.3%",
"of",
"MSI",
"CRCs",
"MSS",
"older",
"carcinoma",
" ",
"was",
"not",
"the",
"most",
"common",
"pathological",
"type,",
"as",
"it",
"only",
"accounted",
"for",
"29%.",
"Interestingly,",
"patients",
"in",
"our",
"MSI-L",
"group",
"were",
"older",
"than",
"the",
"MSS",
"group.",
"The",
"reason",
"for",
"these",
"findings",
"is",
"uncertain.",
"Bettstetter",
"et",
"al.",
"[20]",
"reported",
"that",
"the",
"average",
"age",
"of",
"MSI",
"CRCs",
"with",
"MLH1",
"negative",
"staining",
"CRCs",
"MSI",
"HNPCC",
".",
"In",
"a",
"study",
"by",
"Yearsley",
"et",
"al.",
"[14],",
"out",
"of",
"482",
"US",
"patients",
"with",
"colorectal",
"cancers,",
"87",
"patients",
"(18%)",
"were",
"MSI",
"carriers",
"and",
"only",
"12",
"cases",
"(2.5%)",
"had",
"MMR",
"gene",
"germline",
"mutations.",
"These",
"results",
"may",
"be",
"explained",
"by",
"different",
"case",
"selections",
"and",
"sensitivity",
"of",
"the",
"tests",
"used.",
"On",
"the",
"other",
"hand,",
"in",
"their",
"study",
"of",
"HNPCC",
"related",
"tumors",
"in",
"young",
"patients",
"(<50",
"years",
"old),",
"Niessen",
"et",
"al.",
"[15]",
"found",
"that",
"the",
"rate",
"of",
"MSH2,",
"MSH6",
"and",
"MLH1",
"germline",
"mutations",
"in",
"MSI",
"carriers",
"was",
"82%.",
"In",
"our",
"146",
"patients",
"with",
"colorectal",
"cancers,",
"34",
"patients",
"(23.3%)",
"had",
"MSI",
"colorectal",
"cancer.",
"This",
"is",
"comparable",
"to",
"the",
"studies",
"by",
"Pinol",
"et",
"al.",
"[13]",
"and",
"Yearsley",
"et",
"al.",
"[16].",
"Wong",
"et",
"al.",
"[17]",
"showed",
"that",
"in",
"the",
"case",
"of",
"sporadic",
"endometrial",
"carcinoma,",
"MSI",
"endometrial",
"carcinoma",
"accounted",
"for",
"26%",
"of",
"patients.",
"Our",
"results",
"showed",
"that",
"there",
"were",
"15",
"(10.3%)",
"CRCs",
"with",
"MSI-L",
"and",
"19",
"(13.0%)",
"CRCs",
"with",
"MSL-H,",
"respectively.",
"Lamberti",
"et",
"al.",
"[18]",
"reported",
"that",
"MSI-L",
"and",
"MSI-H",
"accounted",
"for",
"6%",
"and",
"17%,",
"respectively,",
"of",
"German",
"patients.",
"These",
"results",
"are",
"similar",
"to",
"ours.",
"Unexpectedly,",
"in",
"the",
"present",
"study,",
"the",
"age",
"of",
"patients",
"with",
"MSS",
"colorectal",
"cancers",
" ",
"(60",
"yrs)",
"was",
"similar",
"to",
"the",
"age",
"of",
"patients",
"with",
"MSI-H",
"(61",
"yrs).",
"In",
"contrast,",
"the",
"average",
"age",
"of",
"patients",
"with",
"MSI-L",
"colorectal",
"cancer",
"was",
"71,",
"which",
"was",
"quite",
"different",
"from",
"the",
"reports",
"of",
"other",
"research",
"groups",
"[13,15,18].",
"In",
"a",
"study",
"of",
"1263",
"patients",
"with",
"colorectal",
"cancers,",
"Benatti",
"et",
"al.",
"[19]",
"found",
"that",
"those",
"who",
"were",
"MSI",
"carriers",
"tended",
"to",
"have",
"mucinous",
"and",
"right",
"colonic",
"tumours.",
"Noda",
"et",
"al.",
"[20]",
"also",
"found",
"that",
"MSI",
"carriers",
"have",
"more",
"right",
"colonic",
"tumors.",
"However,",
"in",
"our",
"study,",
"tumors",
"in",
"the",
"MSI",
"group",
"were",
"most",
"commonly",
"located",
"at",
"the",
"rectum,",
"and",
"mucinous",
"carcinoma",
"was",
"not",
"the",
"most",
"common",
"pathological",
"type,",
"as",
"it",
"only",
"accounted",
"for",
"29%.",
"Interestingly,",
"patients",
"in",
"our",
"MSI-L",
"group",
"were",
"older",
"than",
"the",
"MSS",
"group.",
"The",
"reason",
"for",
"these",
"findings",
"is",
"uncertain.",
"Bettstetter",
"et",
"al.",
"[20]",
"reported",
"that",
"the",
"average",
"age",
"of",
"MSI",
"CRCs",
"with",
"MLH1",
"negative",
"staining",
"was",
"80",
"yrs,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Most",
"of",
"these",
"MSI",
"CRCs",
"were",
"caused",
"by",
"MLH1",
"promoter",
"hypermethylation.",
"In",
"our",
"group,",
"out",
"of",
"34",
"MSI",
"CRCs,",
"19",
"CRCs",
"(55.9%)",
"were",
"hypermethylated",
"at",
"the",
"MLH1",
"promoter,",
"which",
"accounted",
"for",
"73.7%",
"of",
"MSI-H",
"CRCs",
"and",
"33.3%",
"of",
"MSI",
"CRCs.",
"Anacleto",
"et",
"al.",
"[21]",
"reported",
"that",
"8",
"out",
"of",
"15",
"MSI",
"CRCs",
"had",
"MLH1",
"promoter",
"hypermethylation,",
"which",
"was",
"similar",
"to",
"our",
"results.",
"Kim",
"et",
"al.",
"[10]",
"found",
"that",
"in",
"MSI-H",
"gastric",
"cancers,",
"the",
"MLH1",
"hypermethylation",
"occurred",
"in",
"89%",
"of",
"patients.",
"Bettstetter",
"et",
"al.",
"[20]",
"showed",
"that",
"all",
"sporadic",
"MSI-H",
"CRCs",
"were",
"hypermethylated",
"at",
"the",
"MLH1",
"promoter.",
"These",
"results",
"were",
"similar",
"to",
"ours.",
"Fourteen",
"out",
"of",
"16",
"MLH1",
"negatively",
"staining",
"CRCs",
"were",
"hypermethylated",
"at",
"the",
"MLH1promoter.",
"Mutation",
"analysis",
"revealed",
"that",
"8",
"patients",
"(",
"23.5%",
"CRCs",
"CRCs",
"HNPCC",
".",
"In",
"2004,",
"the",
"NCI",
"recommended",
"the",
"revised",
"Bethesda",
"criteria",
"as",
"a",
"HNPCC",
"screening",
"guideline",
"and",
"established",
"the",
"HNPCC",
"diagnostic",
"procedures.",
"These",
"guidelines",
"stated",
"that",
"MSI",
"should",
"firstly",
"be",
"identified",
"in",
"colorectal",
"tumor",
"tissue,",
"and",
"then",
"genetic",
"tests",
"would",
"be",
"performed",
"to",
"confirm",
"MMR",
"gene",
"germline",
"mutations",
"in",
"a",
"blood",
"sample",
"[6]."
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] | At present, a number of publications have studied the value of the revised Bethesda criteria and the relevant diagnostic procedures [13,14]. However, there has not been any systematic report on germline mutations of MMR genes in the Chinese population. Moreover, we found that research from some countries have results that, if applied to the NCI recommendations, may have resulted in a missed HNPCC family or low pick-up rate of HNPCC. In a study by Pinol et al. from Spain [13], 287 out of 1222 patients (23.5%) complied with the revised Bethesda standard. Ninety-one patients (7.4%) were MSI carriers, but only 11 patients (0.9%) had germline mutations of MSH2 or MLH1. This means that among this group, only 0.9% of patients could be diagnosed as HNPCC. In a study by Yearsley et al. [14], out of 482 US patients with colorectal cancers, 87 patients (18%) were MSI carriers and only 12 cases (2.5%) had MMR gene germline mutations. These results may be explained by different case selections and sensitivity of the tests used. On the other hand, in their study of HNPCC related tumors in young patients (<50 years old), Niessen et al. [15] found that the rate of MSH2, MSH6 and MLH1 germline mutations in MSI carriers was 82%. In our 146 patients with colorectal cancers, 34 patients (23.3%) had MSI colorectal cancer. This is comparable to the studies by Pinol et al. [13] and Yearsley et al. [16]. Wong et al. [17] showed that in the case of sporadic endometrial carcinoma, MSI endometrial carcinoma accounted for 26% of patients. Our results showed that there were 15 (10.3%) CRCs with MSI-L and 19 (13.0%) CRCs with MSL-H, respectively. Lamberti et al. [18] reported that MSI-L and MSI-H accounted for 6% and 17%, respectively, of German patients. These results are similar to ours. Unexpectedly, in the present study, the age of patients with MSS colorectal cancers (60 yrs) was similar to the age of patients with MSI-H (61 yrs). In contrast, the average age of patients with MSI-L colorectal cancer was 71, which was quite different from the reports of other research groups [13,15,18]. In a study of 1263 patients with colorectal cancers, Benatti et al. [19] found that those who were MSI carriers tended to have mucinous and right colonic tumours. Noda et al. [20] also found that MSI carriers have more right colonic tumors. However, in our study, tumors in the MSI group were most commonly located at the rectum, and mucinous carcinoma was not the most common pathological type, as it only accounted for 29%. Interestingly, patients in our MSI-L group were older than the MSS group. The reason for these findings is uncertain. Bettstetter et al. [20] reported that the average age of MSI CRCs with MLH1 negative staining was 80 yrs, which was similar to our results. Most of these MSI CRCs were caused by MLH1 promoter hypermethylation. In our group, out of 34 MSI CRCs, 19 CRCs (55.9%) were hypermethylated at the MLH1 promoter, which accounted for 73.7% of MSI-H CRCs and 33.3% of MSI CRCs. Anacleto et al. [21] reported that 8 out of 15 MSI CRCs had MLH1 promoter hypermethylation, which was similar to our results. Kim et al. [10] found that in MSI-H gastric cancers, the MLH1 hypermethylation occurred in 89% of patients. Bettstetter et al. [20] showed that all sporadic MSI-H MSI-H MSI 80 yrs , which was similar to our results. Most of these MSI CRCs were caused by MLH1 promoter hypermethylation . In our group, out of 34 MSI CRCs MSI CRCs, 19 CRCs 15 HNPCC related tumors in young patients (<50 years old), Niessen et al. [15] found that the rate of MSH2, MSH6 and MLH1 germline mutations in MSI carriers was 82%. In our 146 patients with colorectal cancers, 34 patients (23.3%) had MSI colorectal cancer. This is comparable to the studies by Pinol et al. [13] and Yearsley et al. [16]. Wong et al. [17] showed that in the case of sporadic endometrial carcinoma, MSI endometrial carcinoma accounted for 26% of patients. Our results showed that there were 15 (10.3%) CRCs with MSI-L and 19 (13.0%) CRCs with MSL-H, respectively. Lamberti et al. [18] reported that MSI-L and MSI-H accounted for 6% and 17%, respectively, of German patients. These results are similar to ours. Unexpectedly, in the present study, the age of patients with MSS colorectal cancers (60 yrs) was similar to the age of patients with MSI-H (61 yrs). In contrast, the average age of patients with MSI-L colorectal cancer was 71, which was quite different from the reports of other research groups [13,15,18]. In a study of 1263 patients with colorectal cancers, Benatti et al. [19] found that those who were MSI carriers tended to have mucinous and right colonic tumours. Noda et al. [20] also found that MSI carriers have more right colonic tumors. However, in our study, tumors in the MSI group were most commonly located at the rectum, and mucinous carcinoma was not the most common pathological type, as it only accounted for 29%. Interestingly, patients in our MSI-L group were older than the MSS group. The reason for these findings is uncertain. Bettstetter et al. [20] reported that the average age of MSI CRCs with MLH1 negative staining was 80 yrs, which was similar to our results. Most of these MSI CRCs were caused by MLH1 promoter hypermethylation. In our group, out of 34 MSI CRCs, 19 CRCs (55.9%) were hypermethylated at the MLH1 promoter , which accounted for 73.7% of MSI-H CRCs and 33.3% of MSI CRCs. Anacleto et al. [21] reported that 8 out of 15 MSI CRCs had MLH1 promoter hypermethylation, which was similar to our results. Kim et al. [10] found that in MSI-H gastric cancers, the MLH1 hypermethylation occurred in 89% of patients. Bettstetter et al. [20] showed that all sporadic MSI-H CRCs were hypermethylated at the MLH1 promoter. These results were similar to ours. Fourteen out of 16 MLH1 negatively staining CRCs were hypermethylated at the MLH1promoter. Mutation analysis revealed that 8 patients (23.5%) had MMR gene germline mutations out of 34 MSI patients. Five patients had MSH2 mutations and 3 had MSH6 mutations, while no MLH1 mutation was found. There were 2 82% . In our 146 patients with colorectal cancers, 34 patients (23.3%) had MSI colorectal cancer. This is comparable to the studies by Pinol et al. [13] and Yearsley et al. [16]. Wong et al. [17] showed that in the case of sporadic endometrial carcinoma, MSI endometrial carcinoma accounted for 26% of patients. Our results showed that there were 15 (10.3%) CRCs with MSI-L and 19 (13.0%) CRCs with MSL-H, respectively. Lamberti et al. [18] reported that MSI-L and MSI-H accounted for 6% and 17%, respectively, of German patients. These results are similar to ours. Unexpectedly, in the present study, the age of patients with MSS colorectal cancers (60 yrs) was similar to the age of patients with MSI-H (61 yrs). In contrast, the average age of patients with MSI-L colorectal cancer was 71, which was quite different from the reports of other research groups [13,15,18]. In a study of 1263 patients with colorectal cancers, Benatti et al. [19] found that those who were MSI carriers tended to have mucinous and right colonic tumours. Noda et al. [20] also found that MSI carriers have more right colonic tumors. However, in our study, tumors in the MSI group were most commonly located at the rectum, and mucinous carcinoma was not the most common pathological type, as it only accounted for 29%. Interestingly, patients in our MSI-L group were older than the MSS group. The reason for these findings is uncertain. Bettstetter et al. [20] reported that the average age of MSI CRCs with MLH1 negative staining was 80 yrs, which was similar to our results. Most of these MSI CRCs were caused by MLH1 promoter hypermethylation. In our group, out of 34 MSI CRCs, 19 CRCs (55.9%) were hypermethylated at the MLH1 promoter, which accounted for 73.7% of MSI-H CRCs 26% of patients. Our results showed that there were 15 (10.3%) CRCs with MSI-L and 19 (13.0%) CRCs with MSL-H, respectively. Lamberti et al. [18] reported that MSI-L and MSI-H accounted for 6% and 17%, respectively, of German patients. These results are similar to ours. Unexpectedly, in the present study, the age of patients with MSS colorectal cancers (60 yrs) was similar to the age of patients with MSI-H (61 yrs). In contrast, the average age of patients with MSI-L colorectal cancer was 71, which was quite different from the reports of other research groups [13,15,18]. In a study of 1263 patients with colorectal cancers, Benatti et al. [19] found that those who were MSI carriers tended to have mucinous and right colonic tumours. Noda et al. [20] also found that MSI carriers have more right colonic tumors. However, in our study, tumors in the MSI group were most commonly located at the rectum, and mucinous carcinoma was not the most common pathological type, as it only accounted for 29%. Interestingly, patients in our MSI-L group were older than the MSS group. The reason for these findings is uncertain. Bettstetter et al. [20] reported that the average age of MSI CRCs with MLH1 negative staining was 80 yrs, which was similar to our results. Most of these MSI CRCs were caused by MLH1 promoter hypermethylation. In our group, out of 34 MSI CRCs, 19 CRCs (55.9%) were hypermethylated at the MLH1 promoter, which accounted for 73.7% of MSI-H CRCs and 33.3% of MSI CRCs. Anacleto et al. [21] reported that 8 out of 15 MSI CRCs had MLH1 promoter hypermethylation, which was similar to our results. Kim et al. [10] found that in MSI-H gastric cancers, the MLH1 hypermethylation occurred in 89% of patients. Bettstetter et al. [20] showed that all sporadic MSI-H CRCs were hypermethylated at the MLH1 promoter. These results were similar to ours. Fourteen out of 16 MLH1 negatively staining CRCs were hypermethylated at the MLH1promoter. Mutation analysis revealed that 8 patients (23.5%) had MMR gene germline mutations out of 34 MSI patients. Five patients had MSH2 mutations and 3 had MSH6 mutations, while no MLH1 mutation was found. There were 2 and 6 patients who had mutations in MSH2 and MSH6 in the MSI-L and MSI-H groups, respectively. Yearsley et al. [15], in their study of 87 patients with MSI colorectal cancers CRCs with MSI-L and 19 (13.0%) CRCs with MSL-H, respectively. Lamberti et al. [18] reported that MSI-L and MSI-H accounted for 6% and 17%, respectively, of German patients. These results are similar to ours. Unexpectedly, in the present study, the age of patients with MSS colorectal cancers (60 yrs) was similar to the age of patients with MSI-H (61 yrs). In contrast, the average age of patients with MSI-L colorectal cancer colorectal cancer was 71, which was quite different from the reports of other research groups [13,15,18]. In a study of 1263 patients with colorectal cancers, Benatti et al. [19] found that those who were MSI carriers tended to have mucinous and right colonic tumours. Noda et al. [20] also found that MSI carriers have more right colonic tumors. However, in our study, tumors in the MSI group were most commonly located at the rectum, and mucinous carcinoma was not the most common pathological type, as it only accounted for 29%. Interestingly, patients in our MSI-L group were older than the MSS group. The reason for these findings is uncertain. Bettstetter et al. [20] reported that the average age of MSI CRCs with MLH1 negative staining was 80 yrs, which was similar to our results. Most of these MSI CRCs were caused by MLH1 promoter hypermethylation. In our group, out of 34 MSI CRCs CRCs 17% , respectively, of German patients. These results are similar to ours. Unexpectedly, in the present study, the age of patients with MSS colorectal cancers (60 yrs) was similar to the age of patients with MSI-H (61 yrs). In contrast, the average age of patients with MSI-L colorectal cancer was 71, which was quite different from the reports of other research groups [13,15,18]. In a study of 1263 patients with colorectal cancers, Benatti et al. [19] found that those who were MSI carriers tended to have mucinous and right colonic tumours. Noda et al. [20] also found that MSI carriers have more right colonic tumors. However, in our study, tumors in the MSI group were most commonly located at the rectum, and mucinous carcinoma was not the most common pathological type, as it only accounted for 29%. Interestingly, patients in our MSI-L group were older than the MSS group. The reason for these findings is uncertain. Bettstetter et al. [20] reported that the average age of MSI CRCs CRCs with MSL-H, respectively. Lamberti et al. [18] reported that MSI-L and MSI-H accounted for 6% and 17%, respectively, of German patients. These results are similar to ours. Unexpectedly, in the present study, the age of patients with MSS colorectal cancers (60 yrs) was similar to the age of patients with MSI-H (61 yrs). In contrast, the average age of patients with MSI-L colorectal cancer was 71, which was quite different from the reports of other research groups [13,15,18]. In a study of 1263 patients with colorectal cancers, Benatti et al. [19] found that those who were MSI carriers tended to have mucinous and right colonic tumours. Noda et al. [20] also found that MSI carriers have more right colonic tumors. However, in our study, tumors in the MSI group were most commonly located at the rectum, and mucinous rectum MSI group were most commonly located at the rectum, and mucinous carcinoma was not the most common pathological type, as it only accounted for 29%. Interestingly, patients in our MSI-L group were older than the MSS group. The reason for these findings is uncertain. Bettstetter et al. [20] reported that the average age of MSI CRCs with MLH1 negative staining was 80 yrs, which was similar to our results. Most of these MSI CRCs were caused by MLH1 promoter hypermethylation. In our group, out of 34 MSI CRCs, 19 CRCs (55.9%) were hypermethylated at the MLH1 promoter, which accounted for 73.7% of MSI-H CRCs and 33.3% of MSI CRCs MSS older carcinoma was not the most common pathological type, as it only accounted for 29%. Interestingly, patients in our MSI-L group were older than the MSS group. The reason for these findings is uncertain. Bettstetter et al. [20] reported that the average age of MSI CRCs with MLH1 negative staining CRCs MSI HNPCC . In a study by Yearsley et al. [14], out of 482 US patients with colorectal cancers, 87 patients (18%) were MSI carriers and only 12 cases (2.5%) had MMR gene germline mutations. These results may be explained by different case selections and sensitivity of the tests used. On the other hand, in their study of HNPCC related tumors in young patients (<50 years old), Niessen et al. [15] found that the rate of MSH2, MSH6 and MLH1 germline mutations in MSI carriers was 82%. In our 146 patients with colorectal cancers, 34 patients (23.3%) had MSI colorectal cancer. This is comparable to the studies by Pinol et al. [13] and Yearsley et al. [16]. Wong et al. [17] showed that in the case of sporadic endometrial carcinoma, MSI endometrial carcinoma accounted for 26% of patients. Our results showed that there were 15 (10.3%) CRCs with MSI-L and 19 (13.0%) CRCs with MSL-H, respectively. Lamberti et al. [18] reported that MSI-L and MSI-H accounted for 6% and 17%, respectively, of German patients. These results are similar to ours. Unexpectedly, in the present study, the age of patients with MSS colorectal cancers (60 yrs) was similar to the age of patients with MSI-H (61 yrs). In contrast, the average age of patients with MSI-L colorectal cancer was 71, which was quite different from the reports of other research groups [13,15,18]. In a study of 1263 patients with colorectal cancers, Benatti et al. [19] found that those who were MSI carriers tended to have mucinous and right colonic tumours. Noda et al. [20] also found that MSI carriers have more right colonic tumors. However, in our study, tumors in the MSI group were most commonly located at the rectum, and mucinous carcinoma was not the most common pathological type, as it only accounted for 29%. Interestingly, patients in our MSI-L group were older than the MSS group. The reason for these findings is uncertain. Bettstetter et al. [20] reported that the average age of MSI CRCs with MLH1 negative staining was 80 yrs, which was similar to our results. Most of these MSI CRCs were caused by MLH1 promoter hypermethylation. In our group, out of 34 MSI CRCs, 19 CRCs (55.9%) were hypermethylated at the MLH1 promoter, which accounted for 73.7% of MSI-H CRCs and 33.3% of MSI CRCs. Anacleto et al. [21] reported that 8 out of 15 MSI CRCs had MLH1 promoter hypermethylation, which was similar to our results. Kim et al. [10] found that in MSI-H gastric cancers, the MLH1 hypermethylation occurred in 89% of patients. Bettstetter et al. [20] showed that all sporadic MSI-H CRCs were hypermethylated at the MLH1 promoter. These results were similar to ours. Fourteen out of 16 MLH1 negatively staining CRCs were hypermethylated at the MLH1promoter. Mutation analysis revealed that 8 patients ( 23.5% CRCs CRCs HNPCC . In 2004, the NCI recommended the revised Bethesda criteria as a HNPCC screening guideline and established the HNPCC diagnostic procedures. These guidelines stated that MSI should firstly be identified in colorectal tumor tissue, and then genetic tests would be performed to confirm MMR gene germline mutations in a blood sample [6]. |
3034663-04-Results-p01 | [
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] | In the second LS family, the index subject, one sister and one brother with CRC (II-5; II-6; II-7, respectively) had a deleterious variant in MSH6 (c.3013C>T; p.Arg1005X) but did not have the p.Lys618Ala variant. This variant was present in only three of four unaffected nephews (III-2; III-3; III-4) and was inherited from the parental branch, in which there was no familial history of cancer. Individuals III-3 and III-4 inherited also the deleterious variant familial CRC populations did not deviate significantly from that expected for a population in Hardy-Weinberg equilibrium (Table 1). |
1601966-03-Results-p12 | [
"Down-regulation",
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"region",
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] | Down-regulation of mRNA expression in human chromosomal region 14q24.1-14q24.3 β the FOS region (patient counts with coordinate down-regulation). Grayscale cross-comparison plot of down-regulation patterns across patients (analogous to Figures 8, 11, 14). View this plot in conjunction with Figures 30 and 31. Note, that many more patients show down-regulation as indicated by dark spots in this plot than up-regulation as indicated by dark spots in Figure 31. This region has been reported in other studies to be frequently deleted in colon cancer patient counts with coordinate up-regulation). Grayscale cross-comparison plot of up-regulation patterns across patients (analogous to Figures 7, 10, 13). View this plot in conjunction with Figures 30 and 32. |
2386495-05-Discussion-p02 | [
"The",
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"all",
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1557864-01-Abstract-p01 | [
"No",
"MMR",
"inactivation",
"was",
"detected",
"in",
"75",
"ovarian",
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"specimens",
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] | No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR MSH2 , MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines |
3034663-03-Methods-p01 | [
"The",
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"in",
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"52-93",
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"21-87",
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"25-96",
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"42%",
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] | The median age of patients in the sporadic CRC group was 70 years (range, 52-93 years), 47 years (range, 21-87 years) for the familial group and 71 years (range, 25-96 years) for the controls. The sex distribution was 58% men and 42% women for the sporadic CRC group and 53.3% men and 46.7% women for the controls. |
2386495-04-Results-p02 | [
"A",
"case",
"of",
"APC",
"mosaicism"
] | [
0,
0,
0,
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] | A case of APC mosaicism |
1601966-02-Background-p01 | [] | [] | |
2275286-01-Abstract-p01 | [
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"clinically",
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"instability-high",
"(MSI-H)",
"and",
"microsatellite",
"stable",
"(MSS)",
"groups.",
"Immunohistochemical",
"staining",
"for",
"MSH2,",
"MSH6",
"and",
"MLH1",
"on",
"tissue",
"microarrays",
"(TMAs)",
"was",
"performed,",
"and",
"methylation",
"of",
"the",
"MLH1",
"promoter",
"was",
"analyzed",
"by",
"quantitative",
"methylation",
"specific",
"PCR",
"(MSP).",
"Germline",
"mutation",
"analysis",
"of",
"blood",
"samples",
"was",
"performed",
"for",
"MSH2,",
"MSH6",
"and",
"MLH1",
"genes."
] | [
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] | In 146 prospectively recruited consecutive patients with clinically proven colorectal cancer, MSI carriers were identified by analysis of tumor tissue using multiplex fluorescence polymerase chain reaction (PCR) using the NCI recommended panel and classified into microsatellite instability-low (MSI-L), microsatellite instability-high (MSI-H) and microsatellite stable (MSS) groups. Immunohistochemical staining for MSH2, MSH6 and MLH1 on tissue microarrays (TMAs) was performed, and methylation of the MLH1 promoter was analyzed by quantitative methylation specific PCR (MSP). Germline mutation analysis of blood samples was performed for MSH2, MSH6 and MLH1 genes. |
2386495-01-Abstract-p01 | [
"Conclusion"
] | [
0
] | Conclusion |
3034663-04-Results-p01 | [
"Allelic",
"and",
"genotypic",
"frequencies",
"and",
"Hardy-Weinberg",
"equilibrium"
] | [
0,
0,
0,
0,
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] | Allelic and genotypic frequencies and Hardy-Weinberg equilibrium |
3034663-04-Results-p01 | [
"Results",
"of",
"genotyping",
"for",
"the",
"p.Lys618Ala",
"variant",
"using",
"the",
"iPLEX",
"Sequenom",
"(A)",
"and",
"sequencing",
"(B)",
"methods."
] | [
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0,
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] | Results of genotyping for the p.Lys618Ala variant using the iPLEX Sequenom (A) and sequencing (B) methods. |
2275286-04-Results-p02 | [
"The",
"clinical",
"features",
"of",
"MSI",
"patients",
"with",
"MMR",
"gene",
"mutations",
"are",
"shown",
"in",
"Table",
"5.",
"Mean",
"age",
"was",
"58.8",
"years",
"(range:",
"34β78).",
"Six",
"were",
"female",
"and",
"2",
"were",
"male.",
"Only",
"one",
"patient",
"had",
"right",
"side",
"colonic",
" ",
"lesion",
"male",
"MSI-L",
" ",
"and",
"MSI-H",
"MSH2",
" ",
"germline",
"mutations;",
"the",
"clinical",
"features",
"of",
"these",
"patients",
"are",
"summarized",
"in",
"Table",
"5.",
"None",
"of",
"the",
"patients",
"had",
"MLH1",
"gene",
"mutations.",
"Seven",
"patients",
"in",
"the",
"MSI",
"group",
"had",
"A/T",
"heterozygosis",
"in",
"MSH6",
" ",
"codon",
"380",
"of",
"exon",
"5,",
"but",
"it",
"did",
"not",
"cause",
"changes",
"in",
"the",
"amino",
"acid",
"sequence.",
"The",
"germline",
"mutations",
"of",
"the",
"MSI-L",
"and",
"MSI-H",
"CRCs",
"are",
"summarized",
"in",
"Table",
"6.",
"Six",
"CRCs",
"with",
"mutations",
"were",
"MSI-H",
" ",
"and",
"two",
"patients",
"with",
"mutations",
"were",
"MSI-L",
"."
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] | The clinical features of MSI patients with MMR gene mutations are shown in Table 5. Mean age was 58.8 years (range: 34β78). Six were female and 2 were male. Only one patient had right side colonic lesion male MSI-L and MSI-H MSH2 germline mutations; the clinical features of these patients are summarized in Table 5. None of the patients had MLH1 gene mutations. Seven patients in the MSI group had A/T heterozygosis in MSH6 codon 380 of exon 5, but it did not cause changes in the amino acid sequence. The germline mutations of the MSI-L and MSI-H CRCs are summarized in Table 6. Six CRCs with mutations were MSI-H and two patients with mutations were MSI-L . |
1557864-01-Abstract-p01 | [
"Results"
] | [
0
] | Results |
1334229-01-Abstract-p01 | [
"Conclusion"
] | [
0
] | Conclusion |
1334229-03-Methods-p03 | [
"Analysis",
"of",
"the",
"BAT-26",
"mononucleotide",
"repeat",
"was",
"performed",
"in",
"a",
"random",
"sample",
"of",
"tumour",
"specimens",
"from",
"114",
"patients,",
"and",
"a",
"series",
"of",
"48",
"of",
"58",
"tumours",
"that",
"lacked",
"hMLH1",
"expression",
"hMLH1",
" ",
"expression,",
"to",
"assess",
"the",
"concordance",
"between",
"the",
"microsatellite",
"instability",
"marker",
"BAT-26",
"and",
"hMLH1",
"expression.",
"The",
"primer",
"sequences",
"and",
"PCR",
"conditions",
"for",
"the",
"BAT-26",
"mononucleotide",
"repeat",
"were",
"used",
"as",
"described",
"previously",
"[31]."
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] | Analysis of the BAT-26 mononucleotide repeat was performed in a random sample of tumour specimens from 114 patients, and a series of 48 of 58 tumours that lacked hMLH1 expression hMLH1 expression, to assess the concordance between the microsatellite instability marker BAT-26 and hMLH1 expression. The primer sequences and PCR conditions for the BAT-26 mononucleotide repeat were used as described previously [31]. |
1619718-04-Results-p02 | [
"With",
"respect",
"to",
"the",
"25",
"serrated",
"polyps",
"with",
"dysplasia,",
"only",
"five",
"occurred",
"in",
"the",
"proximal",
"colon",
"(up",
"to",
"the",
"splenic",
"flexure).",
"Two",
"of",
"these",
"had",
"BRAF",
"mutation",
"(both",
"Group",
"A)",
"and",
"two",
"had",
"KRAS",
"mutation",
"(both",
"Group",
"B).",
"Seven",
"of",
"the",
"11",
"BRAF",
"mutations",
"occurred",
"in",
"polyps",
"derived",
"from",
"the",
"left",
"colon",
"or",
"rectum",
"(remaining",
"two",
"polyps",
"with",
"BRAF",
"mutation",
"from",
"site",
"unknown).",
"The",
"three",
"Group",
"A",
"SAs",
"with",
"KRAS",
"mutation",
"90%",
" ",
"had",
"either",
"BRAF",
"or",
"KRAS",
"mutation)",
"and",
"SAs",
"(60%",
"had",
"either",
"BRAF",
"or",
"KRAS",
"mutation)",
"(Table",
"1).",
"The",
"frequent",
"finding",
"of",
"either",
"BRAF",
"or",
"KRAS",
"mutations",
"in",
"both",
"types",
"of",
"serrated",
"polyp",
"indicated",
"that",
"MPs",
"and",
"SAs",
"might",
"be",
"heterogeneous",
"lesions.",
"These",
"25",
"serrated",
"polyps",
"with",
"dysplasia",
"were",
"therefore",
"grouped",
"differently.",
"Group",
"A",
"polyps",
"(n",
"=",
"16)",
"included",
"a",
"non-dysplastic",
"serrated",
"component",
"and/or",
"dysplastic",
"epithelium",
"in",
"which",
"the",
"architectural",
"and",
"cytological",
"changes",
"were",
"more",
"reminiscent",
"of",
"HP",
"dysplastic",
"epithelium",
" ",
"in",
"which",
"the",
"architectural",
"and",
"cytological",
"changes",
"were",
"more",
"reminiscent",
"of",
"HP",
"than",
"adenoma",
"(Figure",
"1A,B).",
"Group",
"B",
"polyps",
"(n",
"=",
"9)",
"comprised",
"serrated",
"polyps",
"in",
"which",
"the",
"epithelial",
"dysplasia",
"appeared",
"adenomatous",
"(Figure",
"1C,D).",
"BRAF",
"mutation",
"occurred",
"in",
"10/16",
"Group",
"A",
"polyps",
"but",
"only",
"1/9",
"Group",
"B",
"polyps",
"(P",
"<",
"0.03).",
"KRAS",
"mutation",
"occurred",
"in",
"only",
"3/16",
"Group",
"A",
"polyps",
"but",
"in",
"5/9",
"Group",
"B",
"polyps",
"(P",
"=",
"0.06).",
"In",
"each",
"of",
"the",
"five",
"Group",
"B",
"polyps",
"with",
"KRAS",
"mutation,",
"the",
"adenomatous",
"component",
"showed",
"both",
"villous",
"change",
"and",
"serration."
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] | With respect to the 25 serrated polyps with dysplasia, only five occurred in the proximal colon (up to the splenic flexure). Two of these had BRAF mutation (both Group A) and two had KRAS mutation (both Group B). Seven of the 11 BRAF mutations occurred in polyps derived from the left colon or rectum (remaining two polyps with BRAF mutation from site unknown). The three Group A SAs with KRAS mutation 90% had either BRAF or KRAS mutation) and SAs (60% had either BRAF or KRAS mutation) (Table 1). The frequent finding of either BRAF or KRAS mutations in both types of serrated polyp indicated that MPs and SAs might be heterogeneous lesions. These 25 serrated polyps with dysplasia were therefore grouped differently. Group A polyps (n = 16) included a non-dysplastic serrated component and/or dysplastic epithelium in which the architectural and cytological changes were more reminiscent of HP dysplastic epithelium in which the architectural and cytological changes were more reminiscent of HP than adenoma (Figure 1A,B). Group B polyps (n = 9) comprised serrated polyps in which the epithelial dysplasia appeared adenomatous (Figure 1C,D). BRAF mutation occurred in 10/16 Group A polyps but only 1/9 Group B polyps (P < 0.03). KRAS mutation occurred in only 3/16 Group A polyps but in 5/9 Group B polyps (P = 0.06). In each of the five Group B polyps with KRAS mutation, the adenomatous component showed both villous change and serration. |
2275286-01-Abstract-p01 | [
"Methods"
] | [
0
] | Methods |
2386495-01-Abstract-p01 | [
"Mutation",
"screening",
"of",
"APC",
"and",
"the",
"clinical",
"characterization",
"of",
"96",
"unrelated",
"FAP",
"patients",
"from",
"the",
"Swedish",
"Polyposis",
"Registry",
"was",
"performed.",
"In",
"addition",
"to",
"generally",
"used",
"mutation",
"screening",
"methods,",
"analyses",
"of",
"splicing-affecting",
"mutations",
"and",
"investigations",
"of",
"the",
"presence",
"of",
"low-frequency",
"mutation",
"alleles,",
"indicating",
"mosaics,",
"have",
"been",
"performed,",
"as",
"well",
"as",
"quantitative",
"real-time",
"polymerase",
"chain",
"reaction",
"to",
"detect",
"lowered",
"expression",
"of",
"APC."
] | [
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] | Mutation screening of APC and the clinical characterization of 96 unrelated FAP patients from the Swedish Polyposis Registry was performed. In addition to generally used mutation screening methods, analyses of splicing-affecting mutations and investigations of the presence of low-frequency mutation alleles, indicating mosaics, have been performed, as well as quantitative real-time polymerase chain reaction to detect lowered expression of APC. |
1619718-04-Results-p01 | [
"SSAs",
"were",
"more",
"likely",
"to",
"have",
"BRAF",
"mutation",
"(81%)",
"than",
"either",
"SAs",
"(33%)",
"(P",
"<",
"0.001)",
"or",
"MPs",
"(40%)",
"(P",
"<",
"0.02).",
"KRAS",
"mutation",
"was",
"infrequent",
"among",
"both",
"SSAs",
"(3%)",
"and",
"HPs",
"(4%)",
"(Table",
"1).",
"Patient",
"age,",
"gender",
"and",
"anatomical",
"location",
"were",
"not",
"predictors",
"of",
"BRAF",
"mutation",
"KRAS",
" ",
"and",
"BRAF",
" ",
"mutation"
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] | SSAs were more likely to have BRAF mutation (81%) than either SAs (33%) (P < 0.001) or MPs (40%) (P < 0.02). KRAS mutation was infrequent among both SSAs (3%) and HPs (4%) (Table 1). Patient age, gender and anatomical location were not predictors of BRAF mutation KRAS and BRAF mutation |
1619718-04-Results-p03 | [
"Sixty-two",
"TAs,",
"22",
"TVAs/VAs,",
"15",
"SAs",
"and",
"10",
"MPs",
"were",
"immunostained",
"for",
"p53.",
"Weak",
"expression",
"of",
"nuclear",
"p53",
"occurred",
"frequently",
"within",
"the",
"proliferative",
"compartment",
"in",
"all",
"types",
"of",
"polyps",
"and",
"was",
"ignored.",
"Aberrant",
"p53",
"expression",
"was",
"observed",
"in",
"only",
"four",
"polyps:",
"one",
"TA,",
"one",
"MP",
"(Figure",
"1B)",
"and",
"two",
"SAs",
"(Figure",
"2).",
"Overall,",
"only",
"1/84",
"(1%)",
"conventional",
"adenomas",
"adenomas",
" ",
"with",
"MGMT",
"loss",
"(P",
"<",
"0.04).",
"Since",
"there",
"were",
"few",
"KRAS",
"mutations",
"in",
"this",
"subset",
"and",
"most",
"KRAS",
"mutations",
"(5/7)",
"were",
"GβA,",
"it",
"was",
"not",
"possible",
"to",
"demonstrate",
"an",
"association",
"between",
"MGMT",
"loss",
"and",
"GβA",
"mutation",
"in",
"KRAS."
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] | Sixty-two TAs, 22 TVAs/VAs, 15 SAs and 10 MPs were immunostained for p53. Weak expression of nuclear p53 occurred frequently within the proliferative compartment in all types of polyps and was ignored. Aberrant p53 expression was observed in only four polyps: one TA, one MP (Figure 1B) and two SAs (Figure 2). Overall, only 1/84 (1%) conventional adenomas adenomas with MGMT loss (P < 0.04). Since there were few KRAS mutations in this subset and most KRAS mutations (5/7) were GβA, it was not possible to demonstrate an association between MGMT loss and GβA mutation in KRAS. |
1619718-04-Results-p01 | [
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1601966-03-Results-p08 | [
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1619718-04-Results-p01 | [
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2275286-04-Results-p02 | [
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3034663-05-Discussion-p01 | [
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1334229-03-Methods-p03 | [
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2275286-02-Background-p01 | [
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1619718-01-Abstract-p01 | [
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] | Thirty-two sessile serrated adenomas (SSA), 10 mixed polyps (MP), 15 traditional serrated adenomas (SA), 49 hyperplastic polyps (HP) and 84 adenomas were assessed for mutation of KRAS and BRAF and aberrant expression of p53. The findings were correlated with loss of expression of O-6-methylguanine DNA methyltransferase (MGMT). KRAS mutation occurred more frequently (26.5%) than BRAF mutation (4.8%) in adenomas (P < 0.001) and particularly in adenomas with villous architecture (50%). Loss of expression of MGMT correlated with KRAS mutation in small tubular adenomas (P < 0.04). BRAF mutation was frequent in HPs (67%) and SSAs (81%), while KRAS mutation was infrequent (4% and 3%, respectively). Of MPs and SAs, 72% had either BRAF or KRAS mutation. Aberrant expression of p53 was uncommon overall, but occurred more frequently in MPs and SAs (12%) than adenomas (1%) (P < 0.04) and there was concordant loss of expression of MGMT. |
1373649-03-Methods-p01 | [
"Determination",
"of",
"MSI"
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0,
0,
0
] | Determination of MSI |
1619718-03-Materials-and-methods-p02 | [
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] | KRAS mutation analysis at codons 12 and 13 was performed using direct automated sequencing of a fragment containing codon 12 and 13 in exon 1 of the KRAS gene, amplified using a touchdown polymerase chain reaction (PCR) cycle and hotstart protocol. PCR products were initially purified and then directly sequenced using BigDye version 3.1 dye terminators and an ABI 3100 DNA fragment analyser. The sequence at codon 12 and 13 was determined using Mutation Surveyor (SoftGenetics, State College, PA, USA) software. |
1619718-04-Results-p01 | [
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] | KRAS mutation occurred in 26.5% and BRAF mutation in 4.8% of adenomas (all types) (Table 1) (P < 0.0001). TVAs/VAs were more likely to have KRAS mutation (50%) than TAs < β 10 mm (18%) (P < 0.004) or TAS > β 10 mm in diameter (17%) (P < 0.02). In the case of TAs there was a trend for KRAS mutation to occur more frequently in polyps from the proximal colon (P = 0.08) and in females (P = 0.07). |