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1360090-03-Results-p01 | [
"Associations",
"between",
"BRAF",
"mutation",
"and",
"clinicopathological",
"features",
"of",
"colorectal",
"cancer."
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] | Associations between BRAF mutation and clinicopathological features of colorectal cancer. |
2386495-05-Discussion-p04 | [
"A",
"case",
"of",
"reduced",
"APC",
"expression"
] | [
0,
0,
0,
0,
0,
0
] | A case of reduced APC expression |
2275286-02-Background-p01 | [
"MSI",
"is",
"an",
"important",
"phenotype",
"of",
"MMR",
"gene",
"mutation",
"tumors",
",",
"but",
"have",
"better",
"survival",
"[1,2].",
"It",
"is",
"believed",
"that",
"HNPCC",
"is",
"secondary",
"to",
"a",
"germline",
"mutation",
"resulting",
"in",
"a",
"defective",
"MMR",
"defective",
"MMR",
"gene",
"1β5%",
" ",
"of",
"colorectal",
"cancer",
"[1].",
"HNPCC",
"patients",
"are",
"characterized",
"by",
"earlier",
"symptoms,",
"more",
"mucinous",
"carcinoma,",
"more",
"synchronous",
"and",
"metachronous",
"colorectal",
"tumors",
"and",
"more",
"extra-colonic",
"tumors,",
"but",
"have",
"better",
"survival",
"[1,2].",
"It",
"is",
"believed",
"that",
"HNPCC",
"is",
"secondary",
"to",
"a",
"germline",
"mutation",
"resulting",
"in",
"a",
"defective",
"MMR",
"gene.",
"A",
"defective",
"MMR",
"gene",
"results",
"in",
"increased",
"DNA",
"replication",
"errors",
"and",
"MSI,",
"which",
"causes",
"the",
"occurrence",
"of",
"tumors",
"in",
"different",
"organs,",
"especially",
"in",
"the",
"colorectum.",
"Identification",
"of",
"HPNCC",
"families",
"is",
"important",
"because",
"the",
"diagnosis,",
"treatment",
"and",
"follow",
"up",
"of",
"these",
"individuals",
"should",
"be",
"different",
"from",
"those",
"with",
"sporadic",
"colorectal",
"cancer",
"[2].",
"However,",
"the",
"clinical",
"diagnosis",
"of",
"HNPCC",
"patients",
"is",
"very",
"difficult",
"for",
"lack",
"of",
"specific",
"clinical",
"phenotype.",
"Though",
"Amsterdam",
"criteria",
"I",
"and",
"II",
"were",
"established",
"for",
"HNPCC",
"diagnosis[3,4],",
"many",
"HNPCC",
"families",
"still",
"do",
"not",
"meet",
"the",
"criteria."
] | [
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] | MSI is an important phenotype of MMR gene mutation tumors , but have better survival [1,2]. It is believed that HNPCC is secondary to a germline mutation resulting in a defective MMR defective MMR gene 1β5% of colorectal cancer [1]. HNPCC patients are characterized by earlier symptoms, more mucinous carcinoma, more synchronous and metachronous colorectal tumors and more extra-colonic tumors, but have better survival [1,2]. It is believed that HNPCC is secondary to a germline mutation resulting in a defective MMR gene. A defective MMR gene results in increased DNA replication errors and MSI, which causes the occurrence of tumors in different organs, especially in the colorectum. Identification of HPNCC families is important because the diagnosis, treatment and follow up of these individuals should be different from those with sporadic colorectal cancer [2]. However, the clinical diagnosis of HNPCC patients is very difficult for lack of specific clinical phenotype. Though Amsterdam criteria I and II were established for HNPCC diagnosis[3,4], many HNPCC families still do not meet the criteria. |
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]. |
1619718-05-Discussion-p05 | [
"**",
"IGNORE",
"LINE",
"**"
] | [
0,
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] | ** IGNORE LINE ** |
1334229-03-Methods-p03 | [
"The",
"Ο2",
"test",
"and",
"CramΓ©rs",
"V",
"test",
"were",
"used",
"to",
"estimate",
"the",
"association",
"of",
"the",
"co-occurrence",
"of",
"K-ras",
"and",
"APC",
"gene",
"mutations.",
"Characteristics",
"of",
"patients",
"(age",
"at",
"diagnosis,",
"sex,",
"family",
"history",
"of",
"colorectal",
"cancer)",
"and",
"tumours",
"(tumour",
"sub-localisation,",
"Dukes'",
"stage",
"and",
"tumour",
"differentiation)",
"were",
"compared",
"between",
"patients",
"with",
"and",
"without",
"an",
"activating",
"K-ras",
"or",
"a",
"truncating",
"APC",
"mutation",
"as",
"well",
"as",
"patients",
"harbouring",
"tumours",
"with",
"and",
"without",
"hMLH1",
"expression,",
"using",
"Students",
"T-test",
"(age",
"at",
"diagnosis)",
"and",
"Ο2",
"tests",
"(sex,",
"family",
"history",
"of",
"colorectal",
"cancer,",
"tumour",
"sub-localisation,",
"Dukes'",
"stage",
"and",
"differentiation).",
"Additionally,",
"patient",
"and",
"tumour",
"characteristics",
"of",
"tumours",
"with",
"an",
"activating",
"K-ras",
"and/or",
"a",
"truncating",
"APC",
"mutation",
"were",
"compared",
"to",
"tumours",
"lacking",
"hMLH1",
"expression.",
"All",
"P-values",
"are",
"reported",
"for",
"a",
"two-sided",
"test;",
"P-values",
"of",
"less",
"than",
"0.05",
"were",
"considered",
"to",
"be",
"statistically",
"significant."
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] | The Ο2 test and CramΓ©rs V test were used to estimate the association of the co-occurrence of K-ras and APC gene mutations. Characteristics of patients (age at diagnosis, sex, family history of colorectal cancer) and tumours (tumour sub-localisation, Dukes' stage and tumour differentiation) were compared between patients with and without an activating K-ras or a truncating APC mutation as well as patients harbouring tumours with and without hMLH1 expression, using Students T-test (age at diagnosis) and Ο2 tests (sex, family history of colorectal cancer, tumour sub-localisation, Dukes' stage and differentiation). Additionally, patient and tumour characteristics of tumours with an activating K-ras and/or a truncating APC mutation were compared to tumours lacking hMLH1 expression. All P-values are reported for a two-sided test; P-values of less than 0.05 were considered to be statistically significant. |
3034663-03-Methods-p02 | [
"Tumours",
"from",
"p.Lys618Ala",
"carrier",
"cases",
"in",
"the",
"familial",
"group",
"(seven",
"index",
"subjects",
"and",
"one",
"relative)",
"were",
"also",
"analysed",
"for",
"MLH1",
"protein",
"expression",
"using",
"immunohistochemistry",
"and",
"anti-MLH1",
"antibodies",
"(PharMingen,",
"CA,",
"USA)",
"as",
"described",
"elsewhere",
"[7].",
"Tumour",
"cells",
"were",
"judged",
"negative",
"for",
"protein",
"expression",
"only",
"if",
"they",
"lacked",
"staining",
"in",
"a",
"sample",
"in",
"which",
"normal",
"colonocytes",
"and",
"stroma",
"cells",
"were",
"stained.",
"If",
"no",
"immunostaining",
"of",
"normal",
"tissue",
"could",
"be",
"demonstrated,",
"the",
"results",
"were",
"considered",
"unreliable."
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] | Tumours from p.Lys618Ala carrier cases in the familial group (seven index subjects and one relative) were also analysed for MLH1 protein expression using immunohistochemistry and anti-MLH1 antibodies (PharMingen, CA, USA) as described elsewhere [7]. Tumour cells were judged negative for protein expression only if they lacked staining in a sample in which normal colonocytes and stroma cells were stained. If no immunostaining of normal tissue could be demonstrated, the results were considered unreliable. |
1557864-01-Abstract-p01 | [
"We",
"determined,",
"microsatellite",
"instability",
"(MSI)",
"as",
"a",
"marker",
"for",
"MMR",
"inactivation",
"(analysis",
"of",
"BAT25",
"and",
"BAT26),",
"MLH1",
"promoter",
"methylation",
"status",
"(methylation",
"specific",
"PCR",
"on",
"bisulfite",
"treated",
"DNA)",
"and",
"mRNA",
"expression",
"of",
"MLH1,",
"MSH2,",
"MSH3,",
"MSH6",
"and",
"PMS2",
"(quantitative",
"RT-PCR)",
"in",
"75",
"ovarian",
"carcinomas",
"and",
"eight",
"ovarian",
"cancer",
"cell",
"lines"
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] | We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines |
1334229-03-Methods-p02 | [
"APC",
"mutation",
"analysis"
] | [
0,
0,
0
] | APC mutation analysis |
1619718-04-Results-p02 | [] | [] | |
1619718-02-Introduction-p01 | [
"The",
"addition",
"of",
"molecular",
"profiling",
"to",
"polyp",
"description",
"offers",
"hope",
"of",
"a",
"more",
"objective",
"and",
"therefore",
"reproducible",
"approach",
"to",
"the",
"classification",
"of",
"colorectal",
"adenomas.",
"The",
"genetic",
"evolutionary",
"paradigm",
"envisages",
"a",
"linear",
"sequence",
"of",
"changes",
"beginning",
"with",
"bi-allelic",
"inactivation",
"of",
"APC,",
"followed",
"by",
"oncogenic",
"KRAS",
"mutation",
"and",
"culminating",
"in",
"inactivation",
"of",
"TP53",
"at",
"the",
"transition",
"from",
"adenoma",
"to",
"carcinoma.5",
"While",
"there",
"is",
"good",
"evidence",
"that",
"KRAS",
"mutation",
"is",
"associated",
"with",
"advanced",
"adenoma",
"features6",
"and",
"could",
"therefore",
"be",
"used",
"as",
"objective",
"evidence",
"of",
"aggression,",
"this",
"approach",
"has",
"a",
"number",
"of",
"limitations.",
"First,",
"KRAS",
"mutation",
"also",
"occurs",
"frequently",
"in",
"dysplastic",
"aberrant",
"crypt",
"epithelial",
" ",
"polyps",
"of",
"the",
"colorectum",
"envisages",
"a",
"larger",
"non-neoplastic",
"category",
"of",
"hyperplastic",
"polyps",
"(HPs)",
"that",
"can",
"be",
"safely",
"ignored",
"and",
"a",
"smaller",
"category",
"of",
"neoplastic",
"polyps",
"or",
"adenomas",
"that",
"are",
"precancerous.1",
"With",
"respect",
"to",
"adenomas,",
"it",
"is",
"clear",
"that",
"the",
"majority",
"will",
"not",
"progress",
"to",
"colorectal",
"cancer",
"(CRC).2",
"The",
"risk",
"of",
"cancer",
"developing",
"within",
"an",
"adenoma",
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"with",
"size,",
"grade",
"of",
"dysplasia",
"(synonymous",
"with",
"intraepithelial",
"neoplasia)",
"and",
"villosity.3",
"These",
"features,",
"together",
"with",
"polyp",
"numbers,",
"are",
"also",
"predictive",
"of",
"metachronous",
"neoplasia",
"and",
"may",
"therefore",
"influence",
"the",
"decision",
"to",
"offer",
"follow-up",
"endoscopic",
"surveillance.4",
"However,",
"the",
"grading",
"of",
"dysplasia",
"and",
"estimation",
"of",
"the",
"extent",
"of",
"villous",
"change",
"may",
"not",
"be",
"fully",
"reproducible",
"and",
"it",
"may",
"be",
"difficult",
"to",
"distinguish",
"new",
"from",
"recurrent",
"adenomas.",
"Establishing",
"a",
"risk",
"profile",
"on",
"the",
"basis",
"of",
"the",
"traditional",
"features",
"of",
"adenoma",
"is",
"therefore",
"not",
"always",
"straightforward."
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] | The addition of molecular profiling to polyp description offers hope of a more objective and therefore reproducible approach to the classification of colorectal adenomas. The genetic evolutionary paradigm envisages a linear sequence of changes beginning with bi-allelic inactivation of APC, followed by oncogenic KRAS mutation and culminating in inactivation of TP53 at the transition from adenoma to carcinoma.5 While there is good evidence that KRAS mutation is associated with advanced adenoma features6 and could therefore be used as objective evidence of aggression, this approach has a number of limitations. First, KRAS mutation also occurs frequently in dysplastic aberrant crypt epithelial polyps of the colorectum envisages a larger non-neoplastic category of hyperplastic polyps (HPs) that can be safely ignored and a smaller category of neoplastic polyps or adenomas that are precancerous.1 With respect to adenomas, it is clear that the majority will not progress to colorectal cancer (CRC).2 The risk of cancer developing within an adenoma increases with size, grade of dysplasia (synonymous with intraepithelial neoplasia) and villosity.3 These features, together with polyp numbers, are also predictive of metachronous neoplasia and may therefore influence the decision to offer follow-up endoscopic surveillance.4 However, the grading of dysplasia and estimation of the extent of villous change may not be fully reproducible and it may be difficult to distinguish new from recurrent adenomas. Establishing a risk profile on the basis of the traditional features of adenoma is therefore not always straightforward. |
1557864-03-Methods-p01 | [
"Patients"
] | [
0
] | Patients |
1601966-05-Conclusion-p01 | [] | [] | |
3034663-03-Methods-p01 | [
"DNA",
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2386495-01-Abstract-p01 | [
"Results"
] | [
0
] | Results |
1557864-02-Background-p01 | [
"If",
"it",
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"resistance,",
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"with",
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"Recently,",
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"including",
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"study,",
"have",
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"gene",
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"response",
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"chemotherapy",
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"ovarian",
"cancer",
"[4-6].",
"We",
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"a",
"nine-gene",
"set",
"which",
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"with",
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"and",
"a",
"specificity",
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"One",
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"cell",
"nuclear",
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] | If it would be possible to predict primary platinum resistance, patients might be spared an ineffective but toxic platinum-containing therapy and might benefit from an early therapy with different drugs. Recently, several molecular profiling studies, including our study, have revealed gene sets that can predict response to platinum-based chemotherapy in ovarian cancer [4-6]. We discovered a nine-gene set which predicts response with a sensitivity of 89% and a specificity of 59% [5]. One of these nine genes was proliferating cell nuclear antigen (PCNA). PCNA is a DNA sliding clamp that interacts with several proteins involved in cell cycle control, DNA methylation, DNA replication and DNA repair including mismatch repair [7]. In this study, we have focused on DNA mismatch repair and its role in platinum-based chemotherapy resistance in ovarian cancer. |
3034663-03-Methods-p01 | [
"Genotyping",
"of",
"the",
"MLH1",
"p.Lys618Ala",
"variant"
] | [
0,
0,
0,
0,
0,
0
] | Genotyping of the MLH1 p.Lys618Ala variant |
1334229-03-Methods-p01 | [
"The",
"PALGA",
"reports",
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"used",
"to",
"identify",
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"whom",
"819",
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] | The PALGA reports were used to identify and locate tumour cancer were identified within the cohort, of whom 819 could also be linked to a PALGA report of the lesion. |
1619718-04-Results-p01 | [
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] | KRAS mutation occurred in 26.5% and BRAF mutation in 4.8% of adenomas mutation TVA and one SSA). The three conventional adenomas with mutations of both BRAF and KRAS were among only four adenomas that had any BRAF mutations at all. Mutation frequencies for both KRAS and BRAF were distributed differently across the seven polyp groups (Table 1). |
1557864-03-Methods-p01 | [
"Patients"
] | [
0
] | Patients |
1557864-01-Abstract-p01 | [
"Methods"
] | [
0
] | Methods |
3034663-04-Results-p01 | [
"Pedigree",
"for",
"Family",
"#1",
"(CRC:",
"Colorectal",
"cancer;",
"GC:",
"Gastric",
"cancer;",
"DC:",
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] | Pedigree for Family #1 (CRC: Colorectal cancer; GC: Gastric cancer; DC: Duodenal cancer). |
1619718-04-Results-p03 | [
"Aberrant",
"expression",
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"p53",
"and",
"correlation",
"with",
"MGMT",
"loss"
] | [
0,
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] | Aberrant expression of p53 and correlation with MGMT loss |
1266026-04-Results-p01 | [
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"(Figure",
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"65.2",
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1619718-04-Results-p02 | [
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1557864-03-Methods-p01 | [
"The",
"MTT",
"colorimetric",
"assay,",
"which",
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"the",
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"viable",
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] | The MTT colorimetric assay, which measures the number of viable cells capable of reducing the tetrazolium compound (Sigma-Aldrich, Zwijndrecht, The Netherlands) to a blue formazan product, was used to quantitate the chemosensitivity of the ovarian cancer cell lines to cisplatin. The assay was performed as described previously by us [38]. |
2275286-04-Results-p02 | [
"Clinical",
"features",
"of",
"patients",
"in",
"MSI",
"group",
"with",
"MMR",
"gene",
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] | Clinical features of patients in MSI group with MMR gene mutations |
1266026-01-Abstract-p01 | [
"Results"
] | [
0
] | Results |
1619718-04-Results-p01 | [
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] | Note: no result for KRAS in one sessile serrated adenoma (SSA) and one tubular adenoma ( TA KRAS KRAS SSA and one TA < β 10 mm. Overall, 34 of 188 polyps (18%) had mutation of KRAS. Twenty-eight mutations were in codon 12 (20 GβA, seven GβT and one GβC) and six mutations were in codon 13 (all GβA). One serrated adenoma had two KRAS mutations in codon 12 (GβT at position 35 and TβG at position 36). BRAF mutation at V600E could be assessed in all polyps except for a single TA < β 10 mm. BRAF mutation was found in 82 of 189 polyps (43%). BRAF and KRAS mutations were negatively correlated, with only four polyps having both mutations (two TAs, one TVA and one SSA). The three conventional adenomas with mutations of both BRAF and KRAS were among only four adenomas that had any BRAF mutations at all. Mutation frequencies for both KRAS and BRAF were distributed differently across the seven polyp groups (Table 1). |
1619718-05-Discussion-p04 | [
"The",
"interpretation",
"of",
"immunostaining",
"for",
"p53",
"is",
"problematic",
"insofar",
"as",
"increased",
"expression",
"of",
"the",
"wild-type",
"protein",
"occurs",
"in",
"areas",
"of",
"increased",
"proliferation",
"and",
"must",
"be",
"distinguished",
"from",
"the",
"diffuse",
"and",
"strong",
"nuclear",
"staining",
"associated",
"with",
"retained",
"mutant",
"protein.",
"However,",
"several",
"studies",
"have",
"described",
"low",
"frequencies",
"of",
"p53",
"expression",
"in",
"TAs",
"with",
"low-grade",
"dysplasia45,46",
"and",
"even",
"in",
"VAs.47",
"Conversely,",
"there",
"is",
"general",
"agreement",
"that",
"aberrant",
"p53",
"expression",
"is",
"closely",
"associated",
"with",
"the",
"presence",
"of",
"high-grade",
"dysplasia",
"amounting",
"to",
"carcinoma",
"in",
"situ.34,46,48",
"Aberrant",
"retention",
"of",
"presumed",
"mutant",
"nuclear",
"p53",
"was",
"rarely",
"observed",
"in",
"the",
"present",
"series,",
"although",
"it",
"occurred",
"more",
"frequently",
"in",
"serrated",
"polyps",
"with",
"dysplasia",
"(12%)",
"than",
"in",
"adenomas",
"(1%).",
"One",
"of",
"the",
"polyps",
"with",
"aberrant",
"expression",
"of",
"p53",
"was",
"a",
"mixed",
"polyp",
"with",
"BRAF",
"mutation",
"(Figure",
"1B).",
"Had",
"it",
"not",
"been",
"removed,",
"this",
"polyp",
"may",
"have",
"progressed",
"within",
"a",
"short",
"time",
"frame",
"to",
"the",
"subset",
"of",
"CRC",
"with",
"BRAF",
"mutation,",
"DNA",
"methylation,",
"TP53",
"mutation",
"and",
"DNA",
"microsatellite",
"stable",
"status",
"(a",
"βfusionβ",
"pathway",
"shown",
"in",
"Table",
"3).49,50"
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] | The interpretation of immunostaining for p53 is problematic insofar as increased expression of the wild-type protein occurs in areas of increased proliferation and must be distinguished from the diffuse and strong nuclear staining associated with retained mutant protein. However, several studies have described low frequencies of p53 expression in TAs with low-grade dysplasia45,46 and even in VAs.47 Conversely, there is general agreement that aberrant p53 expression is closely associated with the presence of high-grade dysplasia amounting to carcinoma in situ.34,46,48 Aberrant retention of presumed mutant nuclear p53 was rarely observed in the present series, although it occurred more frequently in serrated polyps with dysplasia (12%) than in adenomas (1%). One of the polyps with aberrant expression of p53 was a mixed polyp with BRAF mutation (Figure 1B). Had it not been removed, this polyp may have progressed within a short time frame to the subset of CRC with BRAF mutation, DNA methylation, TP53 mutation and DNA microsatellite stable status (a βfusionβ pathway shown in Table 3).49,50 |
1601966-03-Results-p04 | [
"20q11.22-q11.23"
] | [
0
] | 20q11.22-q11.23 |
2386495-01-Abstract-p01 | [] | [] | |
1619718-03-Materials-and-methods-p02 | [
"KRAS",
"and",
"BRAF",
"mutations"
] | [
0,
0,
0,
0
] | KRAS and BRAF mutations |
1619718-02-Introduction-p02 | [
"Subsequently,",
"it",
"was",
"argued",
"that",
"HP",
"and",
"SA",
"are",
"related",
"lesions.11",
"The",
"latter",
"could",
"arise",
"within",
"the",
"former",
"(giving",
"a",
"MP)",
"or",
"could",
"develop",
"as",
"de",
"novo",
"SA",
"but",
"through",
"mechanisms",
"shared",
"with",
"HPs.",
"This",
"proposal",
"subsequently",
"received",
"strong",
"support",
"through",
"the",
"demonstration",
"of",
"molecular",
"alterations",
"common",
"to",
"both",
"types",
"of",
"serrated",
"polyp,",
"notably",
"mutation",
"of",
"BRAF",
"and",
"extensive",
"DNA",
"methylation.12",
"This",
"viewpoint",
"was",
"consolidated",
"through",
"the",
"formal",
"recognition",
"of",
"two",
"largely",
"independent",
"pathways",
"of",
"colorectal",
"tumorigenesis:",
"(i)",
"the",
"traditional",
"adenomaβcarcinoma",
"sequence",
"associated",
"with",
"chomosomally",
"unstable",
"CRCs,13",
"and",
"(ii)",
"the",
"βserrated",
"pathwayβ",
"culminating",
"in",
"CRCs",
"with",
"DNA",
"microsatellite",
"instability",
"(MSI),",
"mutation",
"of",
"BRAF",
"and",
"extensive",
"DNA",
"methylation.12,14β20"
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] | Subsequently, it was argued that HP and SA are related lesions.11 The latter could arise within the former (giving a MP) or could develop as de novo SA but through mechanisms shared with HPs. This proposal subsequently received strong support through the demonstration of molecular alterations common to both types of serrated polyp, notably mutation of BRAF and extensive DNA methylation.12 This viewpoint was consolidated through the formal recognition of two largely independent pathways of colorectal tumorigenesis: (i) the traditional adenomaβcarcinoma sequence associated with chomosomally unstable CRCs,13 and (ii) the βserrated pathwayβ culminating in CRCs with DNA microsatellite instability (MSI), mutation of BRAF and extensive DNA methylation.12,14β20 |
3034663-03-Methods-p01 | [
"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."
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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. |
1557864-01-Abstract-p01 | [
"Results"
] | [
0
] | Results |
2275286-03-Methods-p03 | [
"Primers",
"for",
"all",
"exons",
"of",
"MSH2,",
"MLH1",
"and",
"MSH6",
"were",
"designed",
"for",
"PCR",
"amplification",
"as",
"previously",
"reported.",
"PCR",
"amplification",
"was",
"performed",
"using",
"the",
"reagents",
"from",
"ABI",
"Company,",
"following",
"the",
"protocol",
"provided",
"by",
"the",
"company.",
"After",
"amplification,",
"the",
"PCR",
"products",
"were",
"purified",
"by",
"electrophoresis",
"through",
"a",
"1.5%",
"low",
"melting",
"point",
"agarose",
"gel,",
"and",
"then",
"were",
"sequenced",
"on",
"an",
"AB13100-Avant",
"sequencer",
"(Applied",
"Biosystem",
"Shanghai",
"Division)",
"using",
"fluorescently",
"labeled",
"primers,",
"following",
"the",
"protocols",
"supplied",
"by",
"the",
"manufacturer.",
"By",
"comparing",
"the",
"obtained",
"sequence",
"with",
"the",
"known",
"sequence,",
"nonsense,",
"missense,",
"and",
"frameshift",
"mutations",
"were",
"identified.",
"Nonsense",
"and",
"frameshift",
"mutations",
"were",
"considered",
"pathogenic.",
"All",
"missense",
"mutations",
"were",
"screened",
"in",
"50",
"patients",
"with",
"MSS",
"colorectal",
"cancer",
"and",
"50",
"MSH6",
" ",
"genes"
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] | Primers for all exons of MSH2, MLH1 and MSH6 were designed for PCR amplification as previously reported. PCR amplification was performed using the reagents from ABI Company, following the protocol provided by the company. After amplification, the PCR products were purified by electrophoresis through a 1.5% low melting point agarose gel, and then were sequenced on an AB13100-Avant sequencer (Applied Biosystem Shanghai Division) using fluorescently labeled primers, following the protocols supplied by the manufacturer. By comparing the obtained sequence with the known sequence, nonsense, missense, and frameshift mutations were identified. Nonsense and frameshift mutations were considered pathogenic. All missense mutations were screened in 50 patients with MSS colorectal cancer and 50 MSH6 genes |
3034663-04-Results-p02 | [
"The",
"MSI-positive",
"patient",
"from",
"the",
"familial",
"CRC",
"two",
"Colorectal",
" ",
"cancer;",
"ESC:",
"Oesophageal",
"cancer;",
"LC:",
"Lung",
"cancer)."
] | [
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1,
9,
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] | The MSI-positive patient from the familial CRC two Colorectal cancer; ESC: Oesophageal cancer; LC: Lung cancer). |
1557864-06-Conclusion-p01 | [
"Conclusion"
] | [
0
] | Conclusion |
1601966-03-Results-p05 | [
"We",
"observed",
"increased",
"expression",
"of",
"genes",
"in",
"chromosomal",
"region",
"12q14.2-12q22",
"(see",
"Figures",
"15,",
"16,",
"17).",
"The",
"MDM2",
"gene",
"at",
"12q15",
"is",
"a",
"possible",
"target",
"of",
"this",
"misregulation.",
"However,",
"within",
"this",
"large",
"region",
"there",
"is",
"a",
"smaller",
"region",
"at",
"12q21.1-q21.2",
"spanning",
"eight",
"genes",
"that",
"exhibit",
"exceptionally",
"high",
"expression",
"in",
"our",
"tumor",
"samples.",
"Among",
"these",
"is",
"LGR5",
"alias",
"GPR49",
",",
"a",
"G-protein",
"coupled",
"receptor",
"that",
"has",
"large",
"leucine-rich",
"repeats",
"in",
"its",
"N-terminus.",
"We",
"could",
"confirm",
"the",
"up-regulation",
"of",
"GPR49",
"in",
"CRC",
"by",
"quantitative",
"PCR",
"and",
"in-situ",
"hybridization",
"(data",
"not",
"shown).",
"This",
"finding",
"and",
"the",
"exceptional",
"suitability",
"of",
"G-protein-coupled",
"receptors",
"as",
"drug",
"targets",
"make",
"the",
"LGR5/GPR49",
"protein",
"a",
"potential",
"target",
"for",
"future",
"therapeutical",
"approaches.",
"We",
"do",
"not",
"know",
"of",
"any",
"other",
"reports",
"that",
"link",
"this",
"region",
"to",
"CRC."
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] | We observed increased expression of genes in chromosomal region 12q14.2-12q22 (see Figures 15, 16, 17). The MDM2 gene at 12q15 is a possible target of this misregulation. However, within this large region there is a smaller region at 12q21.1-q21.2 spanning eight genes that exhibit exceptionally high expression in our tumor samples. Among these is LGR5 alias GPR49 , a G-protein coupled receptor that has large leucine-rich repeats in its N-terminus. We could confirm the up-regulation of GPR49 in CRC by quantitative PCR and in-situ hybridization (data not shown). This finding and the exceptional suitability of G-protein-coupled receptors as drug targets make the LGR5/GPR49 protein a potential target for future therapeutical approaches. We do not know of any other reports that link this region to CRC. |
3034663-04-Results-p02 | [
"The",
"MSI-positive",
"patient",
"from",
"the",
"familial",
"CRC",
"group",
"showed",
"loss",
"of",
"immunohistochemical",
"expression",
"of",
"MLH1.",
"This",
"is",
"the",
"index",
"subject",
"(II-3)",
"for",
"the",
"third",
"family",
"(Figure",
"4)",
"and",
"no",
"hypermethylation",
"of",
"MLH1",
"Oesophageal",
"cancer",
";",
"LC:",
"Lung",
" ",
"cancer)."
] | [
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21,
1,
2,
0,
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3,
0,
0
] | The MSI-positive patient from the familial CRC group showed loss of immunohistochemical expression of MLH1. This is the index subject (II-3) for the third family (Figure 4) and no hypermethylation of MLH1 Oesophageal cancer ; LC: Lung cancer). |
3034663-05-Discussion-p01 | [] | [] | |
1266026-05-Discussion-p02 | [
"Multistage",
"models",
"are",
"mechanistically",
"different",
"from",
"tumor",
"progression",
"models",
"and",
"more",
"consistent",
"with",
"a",
"hypothesis",
"that",
"mutations",
"acquired",
"early",
"during",
"progression",
"help",
"determine",
"extent",
"of",
"invasion",
"(Figure",
"3).",
"Mutations",
"sequentially",
"accumulate",
"before",
"transformation",
"in",
"both",
"models,",
"but",
"the",
"adenoma-cancer",
"sequence",
"suggests",
"most",
"cancer",
"mutations",
"start",
"to",
"accumulate",
"after",
"the",
"age",
"of",
"50",
"years",
"in",
"adenomas",
"[7].",
"Such",
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1619718-04-Results-p01 | [
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] | Mutation frequencies for both KRAS (P < 0.0001) and BRAF (P < 0.0001) are distributed differently across the seven classes of polyp (see Results for individual comparisons). Distribution of MGMT loss differs across the seven classes of polyp (P < 0.001). |
1373649-03-Methods-p02 | [
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1619718-04-Results-p01 | [
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] | Frequency of KRAS and BRAF mutation and loss of expression of O-6-methylguanine DNA methyltransferase (MGMT) by polyp type |
1266026-05-Discussion-p01 | [
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1601966-03-Results-p11 | [
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1601966-03-Results-p03 | [
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] | Here, estimates of portions of chromosomes that are affected by regional regulation of expression are given. The second column gives the number of genes on a particular chromosome that were included in our analysis. The following columns contain the numbers of genes that are located in deregulated expression islands (up/down). |
1601966-03-Results-p11 | [
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] | The chromosomal region 14q24.3 has been implicated in colorectal cancer several times (see Table 1). We found coordinated down-regulation of expression of genes in 14q24.1-14q24.3 (see Figures 30, 31, 32). The region comprises the MLH3 gene that is linked to hereditary non-polyposis colorectal cancer type 7 (HNPCC7). We note that also the FOS gene encoding one half of the bZIP dimer activator protein (AP-1) at 14q24.3 is strongly down-regulated. FOS is known as an oncogene and its down-regulation is therefore unexpected. However, deletions of 14q24.3 have been linked to metastatic CRC [36]. In combination, these results suggest that there is a class II tumor metastasis suppressor in this region. This class II TSG is probably not MLH3, as its protein function is hardly related to cellular functions promoting metastasis. The functions of several other strongly misregulated proteins, however, make them better candidates for metastasis suppressors. KIAA0317 codes for a predicted transmembrane ubiquitin ligase. Ubiquitin ligases can help to tag misfolded transmembrane proteins in the ER for destruction via the proteasome system [37]. Absence of such a function could result in misexpressed proteins at the cell surface which could promote metastasis. Other potential candidates for metastasis suppressor genes in this region code for the transmembrane Alzheimer protein PSEN1, the GTPase activating protein KIAA0440/SIPA1L1, the PDZ-domain synaptojanin 2-binding protein SYNJ2BP and the developmental regulator and Notch interaction partner NUMB . |
1334229-02-Background-p01 | [
"Genetic",
"instability",
"is",
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"types",
"of",
"cancer",
"[10].",
"Two",
"distinct",
"types",
"of",
"genetic",
"instability",
"appear",
"to",
"occur",
"in",
"colorectal",
"cancer",
"[11]:",
"chromosomal",
"and",
"microsatellite",
"instability.",
"Chromosomal",
"instability",
"results",
"in",
"gains",
"or",
"losses",
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"entire",
"chromosomes",
"or",
"parts",
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"them,",
"and",
"gives",
"rise",
"to",
"aneuploid",
"tumours",
"and",
"occurs",
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"the",
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"cancers.",
"A",
"smaller",
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"colorectal",
"cancers",
"displays",
"microsatellite",
"instability,",
"represented",
"by",
"diploid",
"cells",
"acquiring",
"high",
"mutation",
"rates,",
"and",
"was",
"found",
"to",
"be",
"associated",
"with",
"defective",
"mismatch",
"repair",
"[12].",
"These",
"tumours",
"are",
"less",
"likely",
"to",
"harbour",
"mutations",
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"genes",
"associated",
"with",
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"instable",
"and",
"generally",
"aneuploid",
"tumours,",
"such",
"as",
"APC,",
"K-ras",
"and",
"TP53",
"[13-21],",
"suggesting",
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"these",
"tumours",
"form",
"a",
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"Moreover,",
"microsatellite",
"instable",
" ",
"tumours",
"are",
"found",
"predominantly",
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"the",
"proximal",
"colon",
"[22,23],",
"are",
"more",
"likely",
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"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",
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] | Genetic instability is seen in most types of cancer [10]. Two distinct types of genetic instability appear to occur in colorectal cancer [11]: chromosomal and microsatellite instability. Chromosomal instability results in gains or losses of entire chromosomes or parts of them, and gives rise to aneuploid tumours and occurs in the majority of cancers. A smaller proportion of colorectal cancers displays microsatellite instability, represented by diploid cells acquiring high mutation rates, and was found to be associated with defective mismatch repair [12]. These tumours are less likely to harbour mutations in genes associated with chromosomally instable and generally aneuploid tumours, such as APC, K-ras and TP53 [13-21], suggesting that these tumours form a distinct group. Moreover, microsatellite instable tumours are found predominantly in the proximal colon [22,23], are more likely to occur in patients 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]. |
1266026-05-Discussion-p02 | [
"Multistage",
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"progression",
"models",
"and",
"more",
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"with",
"a",
"hypothesis",
"that",
"mutations",
"acquired",
"early",
"during",
"progression",
"help",
"determine",
"extent",
"of",
"invasion",
"(Figure",
"3).",
"Mutations",
"sequentially",
"accumulate",
"before",
"transformation",
"in",
"both",
"models,",
"but",
"the",
"adenoma-",
"cancer",
" ",
"sequence",
"suggests",
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" ",
"mutations",
"start",
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"accumulate",
"after",
"the",
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" ",
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"[7].",
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"early",
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"each",
"additional",
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"confers",
"incremental",
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"a",
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"tumor",
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"models",
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] | Multistage models are mechanistically different from tumor progression models and more consistent with a hypothesis that mutations acquired early during progression help determine extent of invasion (Figure 3). Mutations sequentially accumulate before transformation in both models, but the adenoma- cancer sequence suggests most cancer mutations start to accumulate after the age of 50 years in adenomas [7]. Such tumor progression imposes purpose to early mutations because each additional mutation confers incremental changes to a non-invasive adenoma phenotype. Therefore, tumor progression models would likely differ between MSI+ and MSI- cancers because their biology and types of mutations are quite different [7,8]. |
1619718-05-Discussion-p04 | [
"KRAS",
"mutation",
"has",
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"linked",
"to",
"the",
"initiation",
"of",
"hyperplastic",
"aberrant",
"crypt",
"foci",
"and",
"small",
"HPs7,38,55",
"and",
"is",
"therefore",
"closely",
"associated",
"with",
"the",
"development",
"of",
"glandular",
"serration.",
"While",
"the",
"acquisition",
"of",
"KRAS",
"mutation",
"is",
"also",
"observed",
"in",
"adenomas",
",",
"this",
"change",
"is",
"correlated",
"with",
"the",
"development",
"of",
"a",
"villous",
"architecture",
"and",
"in",
"some",
"cases",
"the",
"presence",
"of",
"epithelial",
"serration",
"(see",
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"B",
"serrated",
"polyps",
"above).",
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"therefore",
"be",
"conceptually",
"correct",
"to",
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"KRAS",
"mutation",
"as",
"adding",
"a",
"serrated",
"molecular",
"signature",
"to",
"the",
"traditional",
"adenoma",
"MGMT",
" ",
"loss",
"and",
"aberrant",
"expression",
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"p53",
"is",
"supported",
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"the",
"present",
"findings,",
"it",
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"a",
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] | KRAS mutation has been linked to the initiation of hyperplastic aberrant crypt foci and small HPs7,38,55 and is therefore closely associated with the development of glandular serration. While the acquisition of KRAS mutation is also observed in adenomas , this change is correlated with the development of a villous architecture and in some cases the presence of epithelial serration (see Discussion of Group B serrated polyps above). It may therefore be conceptually correct to view KRAS mutation as adding a serrated molecular signature to the traditional adenoma 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. |
1557864-03-Methods-p02 | [
"The",
"methylation",
"specific",
"PCR",
"(MSP)",
"was",
"used",
"to",
"determine",
"the",
"promoter",
"methylation",
"of",
"MLH1",
"after",
"the",
"DNAs",
"were",
"modified",
"with",
"sodium",
"bisulfite",
"using",
"the",
"Ez",
"DNA",
"methylation",
"kit",
"(Zymo",
"research).",
"We",
"designed",
"and",
"optimized",
"primers",
"that",
"are",
"specific",
"for",
"methylated",
"and",
"unmethylated",
"CpG",
"islands",
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"the",
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"Reverse",
"5'-ACCTCAATACCTCGTACTCACG-3';",
"unmethylated:",
"Forward",
"5'-TGAATTAATAGGAAGAGTGGATAGT-3',",
"Reverse",
"5'-CCTCAATACCTCATACTCACA-3').",
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"located",
"within",
"a",
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"important",
"for",
"a",
"maximal",
"transcription",
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"MLH1",
"(including",
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"site",
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"CBF)",
"[41,42],",
"since",
"methylation",
"at",
"this",
"region",
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"most",
"likely",
"to",
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"transcription",
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"the",
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"The",
"PCR",
"mixture",
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"1Γ",
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"buffer",
"(as",
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"[43]),",
"dNTPs",
"(each",
"at",
"5",
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"primers",
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"95Β°C,",
"30",
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"58Β°C",
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"72Β°C)",
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"a",
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"and",
"in",
"addition,",
"the",
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"cancer",
"cell",
"lines",
"SW48",
"with",
"a",
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"MLH1",
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"SW480",
"with",
"an",
"unmethylated",
"MLH1",
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"were",
"used",
"as",
"positive",
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"negative",
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] | The methylation specific PCR (MSP) was used to determine the promoter methylation of MLH1 after the DNAs were modified with sodium bisulfite using the Ez DNA methylation kit (Zymo research). We designed and optimized primers that are specific for methylated and unmethylated CpG islands within the MLH1 promoter (methylated: Forward 5'-CGAATTAATAGGAAGAGCGGATAGC-3', Reverse 5'-ACCTCAATACCTCGTACTCACG-3'; unmethylated: Forward 5'-TGAATTAATAGGAAGAGTGGATAGT-3', Reverse 5'-CCTCAATACCTCATACTCACA-3'). Both primers are located within a region important for a maximal transcription of MLH1 (including the binding site for the transcription factor CBF) [41,42], since methylation at this region is most likely to inhibit transcription of the gene. The PCR mixture contained 1Γ PCR buffer (as described by Herman et al [43]), dNTPs (each at 5 mM), primers (1 pmol/ΞΌl each per reaction), Taq polymerase (0.05 U/ΞΌl) and 100 ng modified DNA in a volume of 25 ΞΌl. Amplification was carried out for 35 cycles (30 sec 95Β°C, 30 sec 58Β°C for methylated and 55Β°C for unmethylated and 30 sec 72Β°C) followed by a final 4 minutes extension at 72Β°C. Controls without DNA were performed and in addition, the colon cancer cell lines SW48 with a methylated MLH1 promoter and SW480 with an unmethylated MLH1 promoter, were used as positive and negative control respectively. |
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).",
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"ages",
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"68.6",
"years",
"for",
"stage",
"A,",
"69.0",
"years",
"for",
"stage",
"B,",
"65.2",
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"for",
"stage",
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"eight",
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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). |
1373649-03-Methods-p01 | [
"Study",
"protocol"
] | [
0,
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] | Study protocol |
1360090-04-Discussion-p01 | [
"The",
"frequencies",
"of",
"BRAF",
"mutation",
"observed",
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"MSI-",
"(",
"4%",
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] | The frequencies of BRAF mutation observed in MSI- ( 4% tumors 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. |
3034663-04-Results-p01 | [
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] | Results of case-control and case-case analyses. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for the p.Lys618Ala variant |
3034663-05-Discussion-p01 | [
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] | Classification of the MLH1 p.Lys618Ala variant according to the InSiGHT database (accessed on 07/2010). |
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 classes Twenty-eight mutations were in codon 12 (20 GβA, seven GβT and one GβC) and six mutations were in codon 13 (all GβA). One serrated adenoma had two KRAS mutations in codon 12 (GβT at position 35 and TβG at position 36). BRAF mutation at V600E could be assessed in all polyps except for a single TA < β 10 mm. BRAF mutation was found in 82 of 189 polyps 82 of 189 polyps (43%). BRAF and KRAS mutations were negatively correlated, with only four polyps having both mutations (two TAs, one TVA and one SSA). The three conventional adenomas with mutations of both BRAF and KRAS were among only four adenomas that had any BRAF mutations at all. Mutation frequencies for both KRAS and BRAF were distributed differently across the seven polyp groups (Table 1). |
1373649-03-Methods-p01 | [
"Three",
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"relatives",
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"and",
"two",
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"a",
"male",
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"adenocarcinoma",
"at",
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"23",
"contacted",
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] | Three first-degree relatives (mother and two sisters) of a male who died of poorly differentiated colorectal adenocarcinoma at age 23 contacted us for genetic counseling. A detailed family and medical history was obtained through interview with the proband relatives and their consent for release of medical records and use of the pathological tissue blocks still available. |
2275286-03-Methods-p03 | [
"Extraction",
"of",
"genomic",
"DNA",
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] | [
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] | Extraction of genomic DNA from blood |
1373649-05-Conclusion-p01 | [
"We",
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"proband's",
" ",
"non-tumor",
"DNA",
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] | We overcame the absence of proband's non-tumor DNA for MSI testing by studying the alleles carried by his progenitors, the natural approach for the research team due its paternity testing background. |
1601966-06-Methods-p04 | [
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"IGNORE",
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3034663-04-Results-p01 | [
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"LS,",
"the",
"index",
"subject",
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"Two",
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"who",
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] | In one of the families with LS, the index subject was heterozygous for a pathogenic MLH1 variant (c.767C>T; p.Arg226X) and the p.Lys618Ala variant. Two of his offspring, who were diagnosed with CRC at the ages of 36 and 39 years, carried the deleterious variant but not the p.Lys618Ala variant. An unaffected daughter (III-12) carried the p.Lys618Ala variant but not the deleterious variant. Two nephews (III-3; III-4) were also diagnosed with CRC at the ages of 30 and 42 years and they carried only the deleterious variant. Two other healthy nephews (III-6; III-7) had the wild types of the two variants (Family #1, Figure 2). |
1557864-01-Abstract-p01 | [
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2386495-04-Results-p02 | [
"Detection",
"of",
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] | Detection of the mosaic c.2700_2701delTC mutation in patient C107. Nucleotide 2700 is indicated with an arrow. (A) The aberrant bands indicated by the bracket were excised from the SSCP/HD gel. The resulting DNA sequence is shown to the right. (B) DNA sequence from DNA extracted from tumor-derived cells from the patient. (C) The DNA sequence from DNA isolated from the patient's blood lymphocytes. |
1334229-03-Methods-p02 | [
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] | The semi-nested PCR products from samples without a truncating APC mutation were screened for mutations using denaturing high-pressure liquid chromatography (dHPLC) on a WAVE 3500 HT system (Transgenomic Inc., UK). WAVE analysis was optimised and validated using specific mutations in cell line DNA, i.e. HCT116 (codon 45: 3 bp deletion) and SW48 (codon 33: CβA) as well as DNA derived from desmoid exon 1 fragment of the K-ras oncogene, spanning codons 8β29 mutation analysis |
3034663-02-Background-p01 | [
"Lynch",
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] | Lynch syndrome (MIM# 120435) (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset colorectal cancer (CRC), cancer of the endometrium and tumours colorectal cancer (CRC), cancer of the endometrium and tumours of the stomach, pancreas, small intestine, ovary, bladder and bile duct [4]. LS-associated tumours strong history of cancer cancer cases in which a causative mutation is identified is far from ideal. All members from a family with a strong history of cancer and no causative mutation detected are included in a surveillance program. Identification of mutations depends on the specific syndrome and the criteria applied to select patients for genetic analyses. |
1557864-01-Abstract-p01 | [
"Results"
] | [
0
] | Results |
1557864-03-Methods-p01 | [
"The",
"MTT",
"colorimetric",
"assay,",
"which",
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3034663-03-Methods-p02 | [
"Statistical",
"analysis"
] | [
0,
0
] | Statistical analysis |
1619718-05-Discussion-p01 | [
"Adenomas"
] | [
0
] | Adenomas |
1619718-05-Discussion-p02 | [
"dysplastic",
"serrated",
"polyps:",
"MP",
"and",
"SA"
] | [
0,
0,
0,
0,
0,
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] | dysplastic serrated polyps: MP and SA |
1266026-05-Discussion-p03 | [
"**",
"IGNORE",
"LINE",
"**"
] | [
0,
0,
0,
0
] | ** IGNORE LINE ** |
1619718-04-Results-p01 | [
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] | Mutation frequencies for both KRAS (P < 0.0001) and BRAF (P < 0.0001) are distributed differently across the seven classes of polyp (see Results for individual comparisons). Distribution of MGMT loss differs across the seven classes of polyp (P < 0.001). |
3034663-04-Results-p01 | [
"There",
"were",
"no",
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"the",
"case-control",
"and",
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1373649-03-Methods-p01 | [
"DNA",
"preparation",
"for",
"genetic",
"testing"
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0,
0,
0,
0,
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1619718-05-Discussion-p02 | [
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0,
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1266026-03-Methods-p01 | [
"**",
"IGNORE",
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0,
0,
0,
0
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1619718-05-Discussion-p03 | [
"ACF,",
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"dysplastic);",
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"hyperplastic",
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"SSA,",
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] | ACF, Aberrant crypt foci (hyperplastic or dysplastic); HP, hyperplastic polyp; SSA, sessile serrated adenoma; SA, serrated adenoma; TA, tubular adenoma. |
1373649-05-Conclusion-p01 | [
"**",
"IGNORE",
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0,
0,
0,
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1334229-01-Abstract-p01 | [] | [] | |
1373649-04-Results-and-discussion-p02 | [
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"and",
"other",
"related",
"cancers.",
"We",
"found",
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"one",
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"and",
"opportune",
"recommendations",
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"Two",
"years",
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",",
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"recommendations",
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1601966-03-Results-p01 | [
"Prior",
"to",
"the",
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"of",
"chromosomal",
"expression",
"domains,",
"we",
"aimed",
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"to",
"extract",
"discrepancies",
"between",
"tumor",
"samples",
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"normal",
"epithelial",
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"clustering",
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"expression",
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] | Prior to the analysis of chromosomal expression domains, we aimed to check whether the quality of our complete array expression data set (> 44 k genes) allows to extract discrepancies between tumor samples and normal epithelial tissues. Purely unsupervised hierarchical clustering of tissue samples based on gene expression vectors can provide such information. The use of the full set of 44 k genes for clustering is not desirable, because of high signal-noise ratios and computational considerations. Therefore, we pre-selected potentially informative genes for hierarchical clustering. We selected only genes which had reliable information about genomic localization and for which probe sets exceeded a minimum expression threshold in at least 20% of the experiments. To enrich informative genes for tissue distinction, we required a minimum standard deviation across all 50 samples. The pre-selection resulted in 514 probe sets. Note that we avoided to pre-select genes based on differential expression between tumor and normal tissue. We applied three rounds of normalization to genes and arrays. Finally, we applied standard centroid hierarchical clustering (Pearson correlation) to this dataset. Two large clusters were revealed (Figure 1). 18 out of 25 normal tissues formed one single cluster. The remaining 8 normal tissues mainly clustered together with matching tumor samples from same patients. This suggests that coalescence between tumor and normal samples from the same patients could be due to patient -specific gene expression characteristics. As the majority of normal samples could be clearly separated from tumors, we concluded that our data set is well suited to explore differences in gene expression between normal and tumor cells of colorectal origin. |
1266026-04-Results-p01 | [
"Mutation",
"number",
"estimates",
"with",
"respect",
"to",
"clinical",
"stage",
"may",
"be",
"biased",
"with",
"the",
"Finnish",
"data",
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"it",
"includes",
"only",
"specimens",
"with",
"tissue",
"available",
"for",
"molecular",
"analysis.",
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"cancers",
"may",
"not",
"be",
"removed.",
"Therefore,",
"a",
"similar",
"analysis",
"was",
"performed",
"on",
"a",
"population-based",
"cancer",
"MLH1",
"colorectal",
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" ",
"obtained",
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"large",
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"127",
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] | Mutation number estimates with respect to clinical stage may be biased with the Finnish data because it includes only specimens with tissue available for molecular analysis. Advanced cancers may not be removed. Therefore, a similar analysis was performed on a population-based cancer MLH1 colorectal cancers obtained from nine large regional hospitals in southeastern Finland [9]. There were 895 (87.6%) MSI- cancers and 127 (12.4%) MSI+ cancers. The MSI+ cancers were further classified as sporadic (N = 98 or 9.6% of all cancers) or HNPCC (N = 29 or 2.9% of all cancers) based on germline MLH1 or MSH2 mutations (Table 1). |
3034663-03-Methods-p01 | [
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"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. |
1266026-04-Results-p01 | [
"Mutation",
"number",
"estimates",
"with",
"respect",
"to",
"clinical",
"stage",
"may",
"be",
"biased",
"with",
"the",
"Finnish",
"data",
"because",
"it",
"includes",
"only",
"specimens",
"with",
"tissue",
"available",
"for",
"molecular",
"analysis.",
"Advanced",
"cancers",
"may",
"not",
"be",
"removed.",
"Therefore,",
"a",
"similar",
"analysis",
"was",
"performed",
"on",
"a",
"population-based",
"cancer",
"registry",
"[10]",
"from",
"the",
"United",
"States",
"of",
"America",
"(SEER",
"11",
"Regs",
"Public-Use,",
"Nov",
"2001",
"Sub",
"(1992β1999)),",
"which",
"records",
"ages",
"and",
"stages",
"at",
"diagnosis",
"regardless",
"of",
"treatment",
"(Table",
"2).",
"The",
"average",
"age",
"at",
"diagnosis",
"was",
"70.5",
"years,",
"consistent",
"with",
"an",
"estimate",
"of",
"six",
"mutations",
"to",
"colorectal",
"cancer",
"for",
"the",
"108,275",
"white",
"males",
"and",
"females",
"with",
"stage",
"data.",
"Like",
"the",
"Finnish",
"cancers,",
"ages",
"were",
"similar",
"for",
"SEER",
"patients",
"of",
"different",
"clinical",
"stages,",
"with",
"an",
"estimate",
"of",
"six",
"mutations",
"for",
"cancers",
"with",
"localized,",
"regional",
"or",
"distant",
"clinical",
"stages",
"(Table",
"2",
"and",
"Figure",
"1C)."
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] | Mutation number estimates with respect to clinical stage may be biased with the Finnish data because it includes only specimens with tissue available for molecular analysis. Advanced cancers may not be removed. Therefore, a similar analysis was performed on a population-based cancer registry [10] from the United States of America (SEER 11 Regs Public-Use, Nov 2001 Sub (1992β1999)), which records ages and stages at diagnosis regardless of treatment (Table 2). The average age at diagnosis was 70.5 years, consistent with an estimate of six mutations to colorectal cancer for the 108,275 white males and females with stage data. Like the Finnish cancers, ages were similar for SEER patients of different clinical stages, with an estimate of six mutations for cancers with localized, regional or distant clinical stages (Table 2 and Figure 1C). |
1557864-03-Methods-p02 | [
"Quantitative",
"RT-PCR"
] | [
0,
0
] | Quantitative RT-PCR |
2275286-04-Results-p02 | [
"Clinical",
"features",
"of",
"patients",
"in",
"the",
"MSI",
"group",
"with",
"MMR",
"gene",
"mutations"
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Clinical features of patients in the MSI group with MMR gene mutations |
1557864-01-Abstract-p01 | [
"Background"
] | [
0
] | Background |
1619718-01-Abstract-p01 | [
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"traditional",
"serrated",
"adenomas",
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"84",
"adenomas",
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"for",
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"and",
"BRAF",
"and",
"aberrant",
"expression",
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"p53.",
"The",
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"loss",
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"expression",
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"DNA",
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"(MGMT).",
"KRAS",
"mutation",
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"frequently",
"(26.5%)",
"than",
"BRAF",
"mutation",
"(4.8%)",
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"adenomas",
"(P",
"<",
"0.001)",
"and",
"particularly",
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"adenomas",
"with",
"villous",
"architecture",
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"(P",
"<",
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"BRAF",
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"and",
"SSAs",
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"while",
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"and",
"3%,",
"respectively).",
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"15",
"traditional",
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"adenomas",
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"49",
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"84",
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"for",
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"and",
"BRAF",
"and",
"aberrant",
"expression",
"of",
"p53.",
"The",
"findings",
"were",
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"loss",
"of",
"expression",
"of",
"O-6-methylguanine",
"DNA",
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"(MGMT).",
"KRAS",
"mutation",
"occurred",
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"frequently",
"(",
"26.5%",
"84",
" ",
"adenomas",
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"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%",
"KRAS",
"mutation",
"Advanced",
" ",
"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) 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 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% 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% KRAS mutation Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a βfusionβ pathway to colorectal cancer |
2386495-05-Discussion-p03 | [
"Splice-site",
"affecting",
"mutations"
] | [
0,
0,
0
] | Splice-site affecting mutations |
1334229-03-Methods-p01 | [
"Methods"
] | [
0
] | Methods |
1619718-04-Results-p03 | [
"Aberrant",
"expression",
"of",
"p53",
"and",
"correlation",
"with",
"MGMT",
"loss"
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Aberrant expression of p53 and correlation with MGMT loss |
2386495-05-Discussion-p03 | [
"Two",
"novel",
"germline",
"APC",
"mutations",
"that",
"introduce",
"different",
"cryptic",
"splice",
"sites",
"are",
"characterized",
"in",
"this",
"study.",
"Both",
"mutations",
"result",
"in",
"the",
"aberrant",
"splicing",
"of",
"APC",
"exons",
"7",
"and",
"8",
"and",
"prematurely",
"truncated",
"APC",
"protein,",
"and",
"both",
"are",
"defined",
"as",
"pathogenic.",
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"aberrant",
"splicing",
"identified",
"in",
"patient",
"C496",
"patients",
"cases",
" ",
"that",
"exist",
"[23-25,40].",
"In",
"the",
"family",
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"C107",
"the",
"mutation",
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"the",
"offspring",
"of",
"the",
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"and,",
"thus,",
"this",
"appears",
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"a",
"sporadic",
"case,",
"but,",
"generally,",
"the",
"existence",
"of",
"mosaicism",
"is",
"a",
"risk",
"of",
"error",
"in",
"predictive",
"diagnosis",
"in",
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"[43].",
"In",
"the",
"initial",
"stages,",
"the",
"molecular",
"screening",
"procedure",
"of",
"FAP/AFAP",
"patients",
"uses",
"mainly",
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"methods",
"for",
"analysis",
"of",
"the",
"APC",
"gene",
"in",
"DNA",
"from",
"isolated",
"blood",
"samples.",
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"the",
"chances",
"of",
"detecting",
"pathogenic",
"low-frequency",
"APC",
"mutations",
"that",
"are",
"present",
"only",
"in",
"a",
"small",
"fraction",
"of",
"the",
"peripheral",
"blood",
"cells",
"or",
"only",
"in",
"the",
"colon",
"are",
"poor.",
"Approximately",
"25%",
"of",
"neurofibromatosis",
"type",
"2",
"(NF2)",
"patients",
"have",
"been",
"shown",
"to",
"be",
"cases",
"of",
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"[44].",
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"investigating",
"NF2",
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"mosaicism,",
"the",
"search",
"for",
"constitutional",
"mutations",
"is",
"preferably",
"carried",
"out",
"initially",
"in",
"tumor",
"cells.",
"Detected",
"mutations",
"could",
"subsequently",
"be",
"verified",
"in",
"blood",
"leukocyte",
"samples.",
"However,",
"this",
"approach",
"would",
"not",
"be",
"applicable",
"for",
"FAP",
"mosaisicm",
"as",
"somatic",
"APC",
"mutations",
"are",
"frequently",
"found",
"in",
"tumors."
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] | Two novel germline APC mutations that introduce different cryptic splice sites are characterized in this study. Both mutations result in the aberrant splicing of APC exons 7 and 8 and prematurely truncated APC protein, and both are defined as pathogenic. The aberrant splicing identified in patient C496 patients cases that exist [23-25,40]. In the family of C107 the mutation has not been passed on to the offspring of the patient and, thus, this appears to be a sporadic case, but, generally, the existence of mosaicism is a risk of error in predictive diagnosis in FAP/AFAP families [43]. In the initial stages, the molecular screening procedure of FAP/AFAP patients uses mainly PCR-based methods for analysis of the APC gene in DNA from isolated blood samples. Therefore, the chances of detecting pathogenic low-frequency APC mutations that are present only in a small fraction of the peripheral blood cells or only in the colon are poor. Approximately 25% of neurofibromatosis type 2 (NF2) patients have been shown to be cases of mosaicism [44]. When investigating NF2 mutational mosaicism, the search for constitutional mutations is preferably carried out initially in tumor cells. Detected mutations could subsequently be verified in blood leukocyte samples. However, this approach would not be applicable for FAP mosaisicm as somatic APC mutations are frequently found in tumors. |
1266026-05-Discussion-p01 | [
"In",
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"prior",
"studies,",
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"seven",
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"the",
"pattern",
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"is",
"consistent",
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"five",
"to",
"seven",
"oncogenic",
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] | [
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] | In agreement with prior studies, there were seven mutations estimated for sporadic MSI- Finnish cancers [4], and seven or eight mutations for MSI+ cancers. A requirement for more alterations before tranformation for sporadic MSI+ compared to sporadic MSI- cancers may help explain why sporadic MSI+ cancers cancer epidemiology. Colorectal cancer frequencies increase with age, and the pattern of this increase is consistent with approximately five to seven oncogenic mutations [3-6]. |
3034663-03-Methods-p01 | [
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"co-segregation.",
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"families",
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"the",
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] | Three characterized LS families that fulfilled the Amsterdam II Criteria and that consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. Two families attended the Genetic Counselling in Cancer Units of the Elche and La Fe Hospitals and one family was a member of the EPICOLON cohort [7]. |
2386495-04-Results-p01 | [
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] | Sixty-one different APC 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 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 cancer at diagnosis. The median age in this group was 47.5 (range 45β51) years and none had, despite high age at diagnosis 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 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 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. |
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] | Sixty-one different APC mutations in 81 of the 96 families were identified and 27 of those are novel. We have previously shown that 6 of the 96 patients carried biallelic MUTYH mutations. The 9 mutation-negative cases all display an attenuated or atypical phenotype. Probands with a genotype ( codon 1250β1464 9 biallelic MUTYH mutations 6 of the 96 adenomatous polyposis families |