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1619718-01-Abstract-p01 | [
"Aim"
] | [
0
] | Aim |
1360090-03-Results-p01 | [
"(A)",
"Representative",
"F-SSCP",
"gel",
"used",
"to",
"detect",
"BRAF",
"mutationsin",
"colorectal",
"cancer.",
"WT,",
"wild-type;",
"M,",
"mutation.",
"(B)",
"DNA",
"sequencing",
"gel",
"resultconfirms",
"the",
"presence",
"of",
"a",
"1799T",
"to",
"A",
"mutation",
"giving",
"rise",
"to",
"the",
"V600E",
"mutation."
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] | (A) Representative F-SSCP gel used to detect BRAF mutationsin colorectal cancer. WT, wild-type; M, mutation. (B) DNA sequencing gel resultconfirms the presence of a 1799T to A mutation giving rise to the V600E mutation. |
1619718-04-Results-p01 | [
"Note:",
"no",
"result",
"for",
"KRAS",
"in",
"one",
"sessile",
"serrated",
"adenoma",
"(SSA)",
"and",
"one",
"tubular",
"adenoma",
"(TA)",
"or",
"for",
"BRAF",
"in",
"one",
"mutation",
"serrated",
" ",
"adenoma",
"had",
"two",
"KRAS",
"mutations",
"in",
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"12",
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"at",
"position",
"35",
"and",
"T→G",
"at",
"position",
"36).",
"BRAF",
"mutation",
"at",
"V600E",
"could",
"be",
"assessed",
"in",
"all",
"polyps",
"except",
"for",
"a",
"single",
"TA",
"<",
" ",
"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)."
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] | Note: no result for KRAS in one sessile serrated adenoma (SSA) and one tubular adenoma (TA) or for BRAF in one mutation serrated adenoma had two KRAS mutations in codon 12 (G→T at position 35 and T→G at position 36). BRAF mutation at V600E could be assessed in all polyps except for a single TA < 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). |
1557864-03-Methods-p01 | [
"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",
"ovarian",
" ",
"cancer",
"cell",
"line",
"A2780",
"has",
"been",
"cultured",
"separately",
"in",
"two",
"different",
"research",
"laboratories",
"at",
"our",
"department.",
"The",
"isolated",
"DNA",
"and",
"RNA",
"from",
"each",
"culture",
"were",
"used",
"for",
"further",
"analysis."
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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 ovarian cancer cell line A2780 has been cultured separately in two different research laboratories at our department. The isolated DNA and RNA from each culture were used for further analysis. |
1619718-01-Abstract-p01 | [
"Jass",
"J",
"R,",
"Baker",
"K,",
"Zlobec",
"I,",
"Higuchi",
"T,",
"Barker",
"M,",
"Buchanan",
"D",
"&",
"Young",
"J",
"(2006)",
"Histopathology",
"49,",
"121–131"
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] | Jass J R, Baker K, Zlobec I, Higuchi T, Barker M, Buchanan D & Young J (2006) Histopathology 49, 121–131 |
3034663-04-Results-p02 | [
"Of",
"the",
"17",
"CRC",
"patients",
"with",
"the",
"Lys618Ala",
"variant,",
"two",
"had",
"MSI",
"(11.8%),",
"one",
"in",
"the",
"familial",
"CRC",
"group",
"(1/8)",
"and",
"one",
"in",
"the",
"sporadic",
"CRC",
"group",
"(1/9)."
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] | Of the 17 CRC patients with the Lys618Ala variant, two had MSI (11.8%), one in the familial CRC group (1/8) and one in the sporadic CRC group (1/9). |
1334229-05-Discussion-p01 | [
"The",
"selection",
"of",
"patients",
"included",
"in",
"this",
"study",
"was",
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"on",
"the",
"completeness",
"of",
"analyses",
"of",
"both",
"APC",
"and",
"K-ras",
"genes",
"as",
"well",
"as",
"hMLH1",
"expression",
"and",
"this",
"led",
"to",
"a",
"considerable",
"reduction",
"in",
"the",
"number",
"of",
"cases",
" ",
"that",
"could",
"be",
"included",
"in",
"the",
"analyses",
"presented",
"in",
"this",
"study.",
"The",
"largest",
"reduction",
"(72",
"cases)",
"was",
"due",
"to",
"incompleteness",
"of",
"the",
"analysis",
"of",
"all",
"fragments",
"comprising",
"the",
"APC",
"mutation",
"cluster",
"region.",
"Tumour",
"DNA",
"was",
"derived",
"from",
"formalin-fixed,",
"paraffin-embedded",
"tumour",
"tissue",
"blocks.",
"Depending",
"on",
"the",
"conditions",
"of",
"fixation",
"and",
"storage,",
"the",
"extracted",
"DNA",
"is",
"more",
"or",
"less",
"fragmented,",
"which",
"may",
"have",
"impaired",
"the",
"analysis",
"of",
"mutations",
"in",
"the",
"APC",
"gene",
"more",
"than",
"in",
"the",
"K-ras",
"gene,",
"since",
"the",
"analysis",
"of",
"the",
"latter",
"is",
"based",
"on",
"the",
"amplification",
"of",
"a",
"smaller",
"gene",
"fragment.",
"It",
"should",
"be",
"emphasized",
"that",
"characteristics",
"of",
"patients",
"(age,",
"sex,",
"family",
"history",
"of",
"colorectal",
"cancer)",
"and",
"tumours",
"(sub-localisation,",
"Dukes'",
"stage",
"and",
"differentiation)",
"of",
"the",
"group",
"under",
"study",
"are",
"similar",
"to",
"the",
"737",
"patients",
"for",
"whom",
"tumour",
"material",
"was",
"available",
"and",
"to",
"all",
"819",
"patients",
"initially",
"recognized",
"within",
"the",
"cohort",
"(data",
"not",
"shown).",
"Moreover,",
"the",
"K-ras",
"and",
"hMLH1data",
"presented",
"here",
"are",
"similar",
"to",
"the",
"data",
"for",
"K-ras",
"and",
"hMLH1",
"based",
"on",
"the",
"complete",
"groups",
"(737",
"and",
"724",
"cases,",
"respectively)",
"(data",
"not",
"shown)."
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] | The selection of patients included in this study was based on the completeness of analyses of both APC and K-ras genes as well as hMLH1 expression and this led to a considerable reduction in the number of cases that could be included in the analyses presented in this study. The largest reduction (72 cases) was due to incompleteness of the analysis of all fragments comprising the APC mutation cluster region. Tumour DNA was derived from formalin-fixed, paraffin-embedded tumour tissue blocks. Depending on the conditions of fixation and storage, the extracted DNA is more or less fragmented, which may have impaired the analysis of mutations in the APC gene more than in the K-ras gene, since the analysis of the latter is based on the amplification of a smaller gene fragment. It should be emphasized that characteristics of patients (age, sex, family history of colorectal cancer) and tumours (sub-localisation, Dukes' stage and differentiation) of the group under study are similar to the 737 patients for whom tumour material was available and to all 819 patients initially recognized within the cohort (data not shown). Moreover, the K-ras and hMLH1data presented here are similar to the data for K-ras and hMLH1 based on the complete groups (737 and 724 cases, respectively) (data not shown). |
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",
"Patient",
" ",
"codes",
"are",
"given",
"on",
"the",
"vertical",
"axis.",
"The",
"legend",
"depicts",
"which",
"colors",
"code",
"for",
"which",
"expression",
"changes",
"on",
"a",
"loge",
"scale",
"(green:",
"down",
"in",
"tumor;",
"red:",
"up",
"in",
"tumor).",
"View",
"in",
"conjunction",
"with",
"Figures",
"13",
"and",
"14."
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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 Patient codes are given on the vertical axis. The legend depicts which colors code for which expression changes on a loge scale (green: down in tumor; red: up in tumor). View in conjunction with Figures 13 and 14. |
1557864-02-Background-p01 | [
"DNA",
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"repair",
"(MMR)",
"is",
"divided",
"into",
"three",
"steps:",
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"excision",
"and",
"resynthesis",
"(Figure",
"1).",
"Several",
"proteins",
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"involved",
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"the",
"initiation",
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"including",
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"After",
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"recognition",
"of",
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"MLH1",
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"PMS2",
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"leads",
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"initiation",
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"Other",
"known",
"and",
"still",
"unknown",
"proteins",
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"last",
"two",
"steps",
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"MMR,",
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"of",
"the",
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"and",
"the",
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"are",
"recruited",
"subsequently.",
"Proteins",
"known",
"to",
"be",
"involved",
"are",
"exonuclease",
"ExoI,",
"proliferating",
"cell",
"nuclear",
"antigen",
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"DNA",
"polymerase",
"δ",
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"perhaps",
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"addition",
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] | DNA mismatch repair (MMR) is divided into three steps: initiation, excision and resynthesis (Figure 1). Several proteins are involved in the initiation of MMR including the three MutS-homologs, MSH2, MSH3 and MSH6. The MutS homologs form a heterodimer that recognizes DNA damage; the MSH2 and MSH6 dimer (the hMutSα complex) recognizes base-base mismatches and single base loops whereas the MSH2 and MSH3 dimer (hMutSβ complex) recognizes insertion/deletion loops of more then one base. After the recognition of the DNA damage the binding of a heterodimer of the MutS-homologs MLH1 and PMS2 (the hMutLα complex) leads to the further initiation of MMR. Other known and still unknown proteins involved in the last two steps of MMR, the excision of the damaged strand and the resynthesis, are recruited subsequently. Proteins known to be involved are exonuclease ExoI, proliferating cell nuclear antigen (PCNA), DNA polymerase δ and perhaps ε and in addition based on its association with DNA polymerase δ and PCNA, DNA ligase I [8,9]. |
1601966-03-Results-p10 | [
"5q22.2-5q23.1"
] | [
0
] | 5q22.2-5q23.1 |
1334229-03-Methods-p02 | [
"Mutation",
"analysis",
"of",
"the",
"exon",
"1",
"fragment",
"of",
"the",
"K-ras",
"oncogene,",
"spanning",
"codons",
"8–29,",
"was",
"performed",
"on",
"archival",
"colorectal",
"adenocarcinoma",
"specimens",
"of",
"737",
"patients,",
"using",
"nested",
"PCR,",
"followed",
"by",
"direct",
"sequencing",
"of",
"purified",
"fragments",
"[27].",
"The",
"detection",
"limit",
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"5%",
"mutated",
"DNA",
"and",
"duplicate",
"experiments",
"revealed",
"a",
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] | Mutation analysis of the exon 1 fragment of the K-ras oncogene, spanning codons 8–29, was performed on archival colorectal adenocarcinoma specimens of 737 patients, using nested PCR, followed by direct sequencing of purified fragments [27]. The detection limit was 5% mutated DNA and duplicate experiments revealed a good reproducibility (88%) [27]. |
1619718-05-Discussion-p01 | [
"In",
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"KRAS",
"in",
"colorectal",
"adenomas,",
"mutation",
"has",
"been",
"associated",
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"with",
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"depressed",
"TAs",
"and",
"positively",
"with",
"polypoid",
"appearance,",
"increasing",
"size",
"adenoma",
".",
"The",
"current",
"study",
"includes",
"additional",
"types",
"of",
"polyp",
"that",
"are",
"likely",
"to",
"have",
"malignant",
"potential,",
"namely",
"serrated",
"polyps",
"with",
"(MP",
"and",
"SA)",
"and",
"without",
"(SSA)",
"dysplasia.",
"This",
"discussion",
"will",
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"first",
"on",
"adenomas,",
"second",
"on",
"non-dysplastic",
"serrated",
"polyps",
"and",
"will",
"then",
"conclude",
"with",
"the",
"concept",
"that",
"features",
"of",
"these",
"two",
"types",
"of",
"polyp",
"can",
"co-occur",
"or",
"become",
"‘fused’",
"in",
"subtypes",
"of",
"advanced",
"polyps",
"with",
"mixed",
"cytomorphology",
"(hyperplastic",
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"dysplastic)",
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] | In previous studies of KRAS in colorectal adenomas, mutation has been associated negatively with flat and depressed TAs and positively with polypoid appearance, increasing size adenoma . The current study includes additional types of polyp that are likely to have malignant potential, namely serrated polyps with (MP and SA) and without (SSA) dysplasia. This discussion will focus first on adenomas, second on non-dysplastic serrated polyps and will then conclude with the concept that features of these two types of polyp can co-occur or become ‘fused’ in subtypes of advanced polyps with mixed cytomorphology (hyperplastic and dysplastic) and a serrated and/or villous architecture. |
2386495-05-Discussion-p04 | [
"The",
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"next",
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"in",
"patients",
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"no",
"detected",
"APC",
"mutation.",
"Family",
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"is",
"the",
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"the",
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"Polyposis",
"Registry;",
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"includes",
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"57",
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"by",
"the",
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"(Figure",
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"the",
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"no",
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"had",
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"and",
"evidence",
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"expression",
"was",
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"T",
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"diagram",
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"but",
"no",
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"change",
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"the",
"pathogenic",
"change",
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"has",
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"reported",
"as",
"a",
"means",
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"gene",
"silencing",
"in",
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"[46-49].",
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"reported.",
"However,",
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"which",
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"which",
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] | The study of mRNA levels was the next step in the line of investigation of the cause of disease in patients with no detected APC mutation. Family 1 is the largest kindred in the Swedish Polyposis Registry; this family includes 150 individuals of whom 57 are affected by the disease (Figure 6 shows part of the pedigree). However, no pathogenic mutation had been detected after screening the whole coding region of the APC gene but as the family did show positive linkage to the APC locus we decided to perform expression analyses and evidence of lowered APC expression was obtained by quantitative real-time PCR (Figure 5A). The result was supported by the indication of a lower expression from the T-allele from analysis of the APC c.5465A > T polymorphism in the cDNA sequencing diagram of two affected family members (Figure 5B). The search for mutations in the DNA sequence of the APC promoters has been initiated, but no pathogenic change has been detected to this date. The possibility of the pathogenic change being epigenetic will have to be investigated further. Hypermethylation of CpG sites in the promoter of APC has been reported as a means of gene silencing in colorectal tumors [46-49]. To the best of the authors' knowledge no germ-line inactivation of APC caused by promoter hypermethylation has been reported. However, cases of pathogenic germline epimutations have been identified in the MLH1 gene, which causes hereditary non-polyposis APC caused by promoter hypermethylation has been reported. However, cases of pathogenic germline epimutations have been identified in the MLH1 gene, which causes hereditary non-polyposis CRC [50,51]. |
1601966-02-Background-p02 | [
"**",
"IGNORE",
"LINE",
"**"
] | [
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] | ** IGNORE LINE ** |
2386495-02-Background-p01 | [
"Different",
"genotype-phenotype",
"correlations",
"in",
"FAP",
"have",
"been",
"suggested",
"[26-28].",
"The",
"classic",
"phenotype",
"is",
"primarily",
"caused",
"by",
"mutations",
"in",
"the",
"central",
"part",
"of",
"the",
"APC",
"gene.",
"Mutations",
"around",
"codon",
"1309",
"cause",
"a",
"severe",
"course",
"of",
"disease",
"with",
"early",
"onset",
"and",
"profuse",
"polyposis.",
"The",
"milder,",
"attenuated",
"form",
"of",
"disease",
"(AFAP),",
"characterized",
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"than",
"100",
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"profuse",
"polyposis",
"disease",
"MAP",
" ",
"is",
"caused",
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"biallelic",
"mutations",
"in",
"the",
"MUTYH",
"(mutY",
"homologue;",
"MIM*604933)",
"gene",
"(1p32.1-p34.3)",
"and",
"is",
"inherited",
"in",
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] | Different genotype-phenotype correlations in FAP have been suggested [26-28]. The classic phenotype is primarily caused by mutations in the central part of the APC gene. Mutations around codon 1309 cause a severe course of disease with early onset and profuse polyposis. The milder, attenuated form of disease (AFAP), characterized by less than 100 adenomas profuse polyposis disease MAP is caused by biallelic mutations in the MUTYH (mutY homologue; MIM*604933) gene (1p32.1-p34.3) and is inherited in a recessive manner [4,5]. |
1360090-03-Results-p01 | [
"We",
"next",
"examined",
"whether",
"the",
"characteristic",
"features",
"of",
"tumors",
"with",
"BRAF",
"mutation",
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"MSI",
"and",
"CIMP",
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"the",
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"[20],",
"the",
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"KRAS",
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"was",
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"MSI+",
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"MSI-",
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"(P",
"=",
"0.034;",
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"3),",
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"the",
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"was",
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"tumors",
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"than",
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"with",
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" ",
"than",
"in",
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"23/275",
"),",
"comparing",
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"frequencies",
"of",
"9–11%",
"reported",
"for",
"other",
"large",
"studies",
"of",
"this",
"tumor",
"type",
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"grade,",
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"appearance",
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"presence",
"of",
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"lymphocytes.",
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"frequencies",
"of",
"BRAF",
"mutation",
"were",
"also",
"observed",
"in",
"females",
"and",
"in",
"node",
"negative",
"tumors",
"but",
"these",
"did",
"not",
"reach",
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] | We next examined whether the characteristic features of tumors with BRAF mutation were still apparent following stratification into MSI and CIMP phenotypes. Although the statistical power of this subgroup analysis was limited, the morphological features of infiltrating lymphocytes, poor histological grade and mucinous appearance were clearly associated with BRAF mutation regardless of tumor MSI status (Table 3). Similarly, these features were each more common in tumors with BRAF mutation in both the CIMP- and CIMP+ subgroups (Table 4). Similar to previous observations in a separate CRC cohort [20], the frequency of KRAS mutation was lower in MSI+ compared to MSI- tumors (P = 0.034; Table 3), while the frequency of TP53 mutation was also considerably lower in MSI+ tumors with wildtype BRAF than in MSI- tumors with wildtype BRAF BRAF than in MSI- 23/275 ), comparing favourably with frequencies of 9–11% reported for other large studies of this tumor type [6,16,17]. The mean age of patients with and without BRAF mutation was identical (Table 1). Strong associations were observed between BRAF mutation and tumor origin in the proximal side of the large bowel, poor histological grade, mucinous appearance and the presence of infiltrating lymphocytes. Higher frequencies of BRAF mutation were also observed in females and in node negative tumors but these did not reach significance. |
1360090-03-Results-p01 | [
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] | Associations between BRAF mutation and clinicopathological features of colorectal mutation infiltrating lymphocytes . Higher frequencies of BRAF mutation were also observed in females and in node negative tumors but these did not reach significance. |
1373649-02-Background-p01 | [
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] | This autosomal dominantly inherited disorder is caused by germline mutations in genes coding proteins responsible for the repair of DNA replication errors, which are referred to as DNA mismatch repair (MMR) genes [5]. DNA mismatch repair machinery plays a critical role in genomic stability, including correction of mispaired bases associated with DNA replication and recombination. Germline mutations in one allele of any of these genes followed by the somatic loss or inactivation of the wild-type allele leads to a defective mismatch repair mechanism. The current "gold standard" for assessing tumor DNA MMR activity is molecular microsatellite instability (MSI) testing. In most cases, it involves extracting DNA from both tumor and normal tissue. The DNA is subjected to polymerase chain reaction (PCR) amplification of five or more different chromosomal loci that compare "microsatellites", running the PCR products through a gel to separate DNA fragments by size, comparing the tumor-normal pairs, and scoring for differences between the two. Instability at two or more out of five markers defines a tumor as MSI-H and prompts further analysis, as sequencing of DNA MMR genes. A number of them have been associated with HNPCC, including hMSH2, hMLH1, hPMS1, hPMS2, hMSH3, and hMSH6. Most of the HNPCC families family fulfill the following criteria (referred to as the Amsterdam-I criteria [3]): 1. Three or more relatives with histologically verified colorectal cancer, one of whom is a first-degree relative of the other two; 2. Colorectal cancer affecting at least 2 successive generations; and 3. At least one relative diagnosed with colorectal cancer under the age of 50. The fulfillment of these criteria prompted further genetics investigations. More recently it has been revised to take into account the prevalence of extracolonic cancer in certain HNPCC families [4]. |
1266026-01-Abstract-p01 | [
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] | Different biologic subtypes of colorectal cancer seven or eight mutations for its sporadic counterpart. Ages at cancer were consistent with seven mutations for sporadic MSI- cancers, and were similar (six to eight mutations) regardless of clinical cancer stage. |
1601966-06-Methods-p02 | [
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3034663-03-Methods-p01 | [
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1373649-04-Results-and-discussion-p01 | [
"Although",
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] | Although BAT-26 has been reported to be sufficient for MSI-H detection even without normal tissue matching [9], careful interpretation is needed if MSI-H detection is based solely on this marker, since polymorphism at the BAT-26 locus has been detected [10]. |
1619718-05-Discussion-p01 | [
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1619718-05-Discussion-p04 | [
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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 and hence providing an additional ‘fusion’ pathway. However, a mechanistic link between KRAS mutation and the morphogenesis of serration and villous change remains to be established. MGMT BRAF 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 ‘fusion’ pathway shown in Table 3).49,50 |
3034663-03-Methods-p01 | [
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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. |
1601966-03-Results-p10 | [
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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 mutation BRAF TA < 10 mm . Overall, 34 of 188 polyps (18%) had mutation of KRAS. Twenty-eight mutations were in codon 12 (20 G→A, seven G→T and one G→C) and six mutations were in codon 13 (all G→A). One serrated adenoma had two KRAS mutations in codon 12 (G→T at position 35 and T→G at position 36). BRAF mutation at V600E could be assessed in all polyps except for a single TA < 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). |
1619718-04-Results-p02 | [
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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 (all from the left colon or rectum) comprised numerous goblet cells and adjacent cells with eosinophilic cytoplasm and no mucin production or microvesicular appearance adjacent cells with eosinophilic cytoplasm 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. |
1334229-02-Background-p01 | [
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1557864-05-Discussion-p03 | [
"Next",
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"the",
"eleven",
"patients",
"could",
"not",
"be",
"associated",
"with",
"MSI",
"and",
"MMR",
"inactivation."
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] | Next we addressed the second part of the aim of this study, is MMR inactivation associated with resistance to platinum-based chemotherapy in ovarian cancer. Forty-six of the 75 ovarian carcinomas we analyzed had been treated with platinum-based chemotherapy, eleven did not respond and 34 did. For one patient the response was not known. Methylation of the MLH1 promoter was detected in two of the eleven non-responders (18%) and four of the 34 responders (12%) and this was not significantly different (p = 0.664). Since we did not detect any MSI, the resistance seen in the eleven patients could not be associated with MSI and MMR inactivation. |
3034663-04-Results-p01 | [
"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)."
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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). |
1601966-03-Results-p02 | [] | [] | |
2275286-06-Conclusion-p01 | [] | [] | |
1601966-03-Results-p10 | [
"Not",
"unexpected,",
"we",
"found",
"loss",
"of",
"expression",
"in",
"region",
"5q22.2-5q23.1",
"(see",
"Figures",
"27,",
"28,",
"29).",
"This",
"interval",
"harbors",
"two",
"known",
"TSGs",
"in",
"colon",
"cancer,",
"the",
"adenomatous",
"polyposis",
"coli",
"gene",
"(APC)",
"gene",
"and",
"the",
"mutated",
"in",
"colorectal",
"cancer",
" ",
"(MCC).",
"We",
"were",
"not",
"able",
"to",
"obtain",
"expression",
"values",
"for",
"APC.",
"APC",
"is",
"located",
"at",
"the",
"border",
"of",
"a",
"region",
"at",
"5q22.2-5q22.3",
"that",
"harbors",
"several",
"drastically",
"down-regulated",
"genes.",
"Central",
"in",
"this",
"region",
"is",
"the",
"MCC",
"colon",
"cancer",
" ",
"(see",
"Table",
"4).",
"Note",
"the",
"expression",
"down-regulation",
"of",
"BCL2.",
"SMAD4",
"(Hs.298320)",
"and",
"TCF4",
"are",
"only",
"weakly",
"down-regulated.",
"The",
"DCC",
"gene",
"is",
"also",
"located",
"in",
"this",
"region",
"between",
"LOC51320",
"and",
"MBD2",
"but",
"no",
"informative",
"expression",
"measures",
"were",
"obtained."
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] | Not unexpected, we found loss of expression in region 5q22.2-5q23.1 (see Figures 27, 28, 29). This interval harbors two known TSGs in colon cancer, the adenomatous polyposis coli gene (APC) gene and the mutated in colorectal cancer (MCC). We were not able to obtain expression values for APC. APC is located at the border of a region at 5q22.2-5q22.3 that harbors several drastically down-regulated genes. Central in this region is the MCC colon cancer (see Table 4). Note the expression down-regulation of BCL2. SMAD4 (Hs.298320) and TCF4 are only weakly down-regulated. The DCC gene is also located in this region between LOC51320 and MBD2 but no informative expression measures were obtained. |
3034663-03-Methods-p01 | [
"DNA",
"from",
"blood",
"cells",
"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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] | DNA from blood cells 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. |
2386495-04-Results-p02 | [
"DNA",
"sequencing",
"of",
"APC",
"patients",
" ",
"(C107,",
"C257,",
"and",
"C505),",
"negative",
"for",
"mutations",
"in",
"APC,",
"were",
"reported",
"as",
"de",
"novo",
"cases",
"with",
"no",
"known",
"family",
"history",
"of",
"FAP.",
"These",
"patients",
" ",
"where",
"all",
"screened",
"for",
"APC",
"mutations",
"present",
"as",
"low-frequency",
"alleles",
"using",
"SSCP/HD.",
"We",
"did",
"not",
"detect",
"any",
"signs",
"of",
"low-frequency",
"mutations",
"in",
"patients",
" ",
"C257",
"and",
"C505.",
"However,",
"in",
"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)."
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] | DNA sequencing of APC patients (C107, C257, and C505), negative for mutations in APC, were reported as de novo cases with no known family history of FAP. These patients where all screened for APC mutations present as low-frequency alleles using SSCP/HD. We did not detect any signs of low-frequency mutations in patients C257 and C505. However, in 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). |
1557864-01-Abstract-p01 | [
"Conclusion"
] | [
0
] | Conclusion |
2275286-01-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",
"people",
"without",
"cancer",
"or",
"a",
"family",
"history",
"of",
"cancer.",
"They",
"were",
"judged",
"as",
"pathogenic",
"if",
"they",
"could",
"not",
"be",
"found",
"in",
"MSS",
"patients",
"MSI",
" ",
"colorectal",
" ",
"cancer,",
"and",
"genomic",
"DNA",
"was",
"extracted",
"using",
"a",
"kit",
"from",
"Beijing",
"Bio-Lab",
"Materials",
"Institute.",
"The",
"extracted",
"genomic",
"DNA",
"was",
"stored",
"at",
"-80°C",
"until",
"further",
"analysis."
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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 people without cancer or a family history of cancer. They were judged as pathogenic if they could not be found in MSS patients MSI colorectal cancer, and genomic DNA was extracted using a kit from Beijing Bio-Lab Materials Institute. The extracted genomic DNA was stored at -80°C until further analysis. |
2275286-03-Methods-p03 | [
"Mutation",
"of",
"MSH2,",
"MLH1",
"and",
"MSH6",
"genes"
] | [
0,
0,
0,
0,
0,
0,
0
] | Mutation of MSH2, MLH1 and MSH6 genes |
3034663-02-Background-p01 | [
"The",
"majority",
"of",
"UVs",
"are",
"missense",
"mutations",
"or",
"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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] | The majority of UVs are missense mutations or 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-p01 | [
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"sessile",
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] | Note: no result for KRAS in one sessile serrated adenoma (SSA) and one tubular adenoma (TA) or for BRAF in one TA. MGMT immunstaining not performed in 15 polyps (seven HPs, one SSA, one MP and six TAs). |
1373649-03-Methods-p01 | [
"Study",
"protocol"
] | [
0,
0
] | Study protocol |
1334229-02-Background-p01 | [
"Background"
] | [
0
] | Background |
2386495-05-Discussion-p03 | [
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] | APC mutational mosaicism could be a reason for the quite large number of de novo or sporadic FAP 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 patient C107. This mutation was detected in a very low fraction of the lymphocytes and was only detectable using the SSCP/HD analysis (Figure 2A). Owing to the subtle appearance of this mutation it could easily have been overlooked. |
2386495-01-Abstract-p01 | [
"Results"
] | [
0
] | Results |
1360090-03-Results-p01 | [
"a",
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"unavailable",
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"cases,",
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"cases,",
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"cases,",
"grade",
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] | a Data was unavailable for gender in 43 cases, infiltrating lymphocytes in 55 cases, nodal involvement in 77 cases, tumor site in 56 cases, grade in 106 cases and mucinous appearance in 89 cases. |
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 < 10 mm (18%) (P < 0.004) or TAS > 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). |
1334229-05-Discussion-p01 | [
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3034663-05-Discussion-p01 | [
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1601966-03-Results-p02 | [
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1266026-05-Discussion-p01 | [
"In",
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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 to appear at different ages. Precisely when and how quickly mutations accumulate are unknown, but a basic premise is that cancer types requiring more mutations will tend to appear later in life. Therefore, numbers of mutations may be estimated from 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]. |
1334229-03-Methods-p01 | [
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"929",
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"were",
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"the",
"cohort,",
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] | Incident cancer cases are identified by monitoring of the entire cohort for cancer occurrence through annual record linkage to the Netherlands Cancer Registry, i.e. nine regional cancer registries throughout the Netherlands, and to PALGA, a nationwide network and registry of histo- and cytopathology [30]. Together, the NCR and PALGA provide a near 100% coverage of the municipalities included in the NLCS. The first 2.3 years of follow up were excluded because of possible pre-clinical disease affecting exposure status and because of incomplete nationwide coverage of PALGA in some of the municipalities included in the NLCS in that period. From 1989 until 1994, 929 incident cases with histologically confirmed colorectal cancer were identified within the cohort, of whom 819 could also be linked to a PALGA report of the lesion. |
2275286-04-Results-p02 | [
"*Amsterdam",
"criteria",
"II"
] | [
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] | *Amsterdam criteria II |
3034663-02-Background-p01 | [
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] | The results of sequence-based genetic tests may be reported to physicians as: 1) positive, in which a mutation that clearly disrupts gene function is detected and is highly likely to have clinical consequences; 2) a genetic variant is detected but it is not known whether the variant has any effect on gene function that might confer an increased cancer risk (these variants are known as variants of uncertain/unclassified significance or unclassified variants [UVs]); and 3) negative, in which deleterious variant or UV is detected [1]. |
3034663-04-Results-p01 | [
"Results",
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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 |
1619718-05-Discussion-p03 | [
"Concept",
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3034663-04-Results-p01 | [
"Pedigree",
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"cancer;",
"GC:",
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"DC:",
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1619718-04-Results-p01 | [
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1334229-04-Results-p01 | [
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] | Of 656 tumours for which the other molecular alterations, i.e. mutations in the APC and K-ras genes and hMLH1 expression, were all successfully and completely analysed, 103 colorectal tumours did not harbour a truncating or missense APC mutation, an activating K-ras mutation or showed lack of hMLH1 expression, as depicted in figure 1. Truncating as well as missense APC mutations and activating K-ras mutations were relatively common. Truncating APC mutations alone and activating K-ras mutations in codons 12 and 13 only, occurred at similar frequencies (20% (130/656) and 18% (121/656), respectively). A combination of a truncating mutation in APC and an activating mutation in K-ras occurred less often than the sole occurrences of mutations in both genes. However, as shown in table 2, the simultaneous occurrence of mutations in both genes occurred more frequently than expected on the basis of chance alone. A χ2 test for the occurrence of a truncating APC mutation and an activating K-ras mutation revealed that the occurrence of these mutations was not independent (χ2 = 8.7, P < 0.001), but the correlation was weak (Cramérs V = 0.138). Finally, although 11 tumours colorectal cancers , a CTNNB1 mutation that would lead to loss of one of the Ser/Thr phosphorylation sites and subsequent stabilisation of the protein, occurred at codons 37 and 45, all were C→T transitions, leading to Ser→Phe amino acid changes and occurred in the proximal colon. All bar one also had an activating mutation in the K-ras gene. Three of these five tumours showed hMLH1 deficiency. Two colorectal cancer patients harboured a mutation in the CTNNB1 gene, that did not occur at the Ser/Thr phosphorylation sites, but would result in an amino acid alteration at codons 22 and 29, the effects of which are unknown. Because of the very low frequency of tumours tumours showed hMLH1 deficiency. Two colorectal cancer patients harboured a mutation in the CTNNB1 gene, that did not occur at the Ser/Thr phosphorylation sites, but would result in an amino acid alteration at codons 22 and 29, the effects of which are unknown. Because of the very low frequency of tumours harbouring a CTNNB1 mutation, these mutations were not included in further analyses. In addition, mutation analysis of remaining samples was abandoned, since this was deemed irrelevant as these harboured truncating APC mutations and are considered to be unlikely to also have CTNNB1 mutations [7]. |
1557864-03-Methods-p01 | [
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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]. |
1619718-05-Discussion-p01 | [
"Adenomas"
] | [
0
] | Adenomas |
1334229-04-Results-p01 | [
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1334229-01-Abstract-p01 | [
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1601966-03-Results-p03 | [
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"[27,28].",
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] | Gain of expression in region 8q11.23-q21.13 is strongest in a small interval (8q12.1) that spans genes from TCEA1 to PLAG1 (see Figures 6, 7, 8). There have been numerous reports of copy number gains of chromosome 8q in CRC [18,21,23,25] which suggests a possible mechanism leading to over-expression in our patients. The known blood cell oncogene LYN is located in this interval and it is up-regulated in several of our tumor samples. It has been reported before that LYN is expressed in colorectal tumors [26]. The concerted up-regulation of LYN along with other genes in this region suggests a role for LYN in CRC. Another interesting gene in this interval is PLAG1 (pleomorphic adenoma gene 1) for which chromosomal aberrations have been described that lead to over-expression in salivary gland tumors [27,28]. No informative expression measures were obtained for the MOS protein kinase gene which is located between RPS20 and PLAG1, although this may be due to technical limitations. Genes encoding components of the translation machinery, the mitochondrial ribosomal protein MRPL15 and cytosolic ribosomal proteins RPL7 and RPS20 PLAG1 RPS20 and PLAG1, although this may be due to technical limitations. Genes encoding components of the translation machinery, the mitochondrial ribosomal protein MRPL15 and cytosolic ribosomal proteins RPL7 and RPS20, are located in this region, highlighting the need for enhanced translation in cancer salivary gland over-expression in salivary gland tumors [27,28]. No informative expression measures were obtained for the MOS protein kinase gene which is located between RPS20 and PLAG1, although this may be due to technical limitations. Genes encoding components of the translation machinery, the mitochondrial ribosomal protein MRPL15 and cytosolic ribosomal proteins RPL7 tumors up-regulation of LYN along with other genes in this region suggests a role for LYN in CRC. Another interesting gene in this interval is PLAG1 (pleomorphic adenoma gene 1) for which chromosomal aberrations Hereditary colorectal cancer syndromes are indicated along with their OMIM ID. Gene symbols are official or provisional HUGO symbols if available, otherwise names of Unigene clusters. Information about known tumor genes in misregulated regions were extracted from the literature. Tumor-associated genes are located within expression islands or in near vicinity. |
1601966-03-Results-p03 | [
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] | These are condensed results of the ChARM analyses: overlapping regions with evidence for up- or down-regulation from various analyses of different cross-correlation window sizes have been fused into single regions. The original ChARM output including p values for each region and additional annotation can be found in Additional file 1. Hereditary colorectal cancer syndromes are indicated along with their OMIM ID. Gene symbols are official or provisional HUGO symbols if available, otherwise names of Unigene clusters. Information about known tumor genes in misregulated regions were extracted from the literature. Tumor-associated genes are located within expression islands or in near vicinity. |
2386495-01-Abstract-p01 | [
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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. |
1557864-03-Methods-p01 | [
"Patients"
] | [
0
] | Patients |
2275286-04-Results-p02 | [
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] | Clinical features of patients in MSI group with MMR gene mutations |
1334229-03-Methods-p01 | [
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] | The PALGA reports were used to identify and locate tumour tissue from eligible colorectal cancer patients in Dutch pathology laboratories. Colon and rectal cancer were classified according to site as follows, colon: cecum through sigmoid colon (ICD-O codes 153.0, 153.1, 153.2, 153.3, 153.4, 153.5, 153.6, 153.7), rectosigmoid (ICD-O code 154.0), and rectum (ICD-O code 154.1). |
1334229-02-Background-p01 | [
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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 with a positive family history of colorectal cancer [22,23], are often less differentiated than microsatellite stable tumours [22], and occur more frequently in women [24] and at older age [25]. Moreover, in tumours displaying microsatellite instability, mutations mutations Activation of the Ras pathway in cancer is marked by the loss of the intrinsic GTPase activity of the Ras protein, which can be ascribed to missense mutations in codons 12 and 13 of exon 1, which are responsible for 90% activating mutations in the of the K-ras gene [8]. |
3034663-04-Results-p01 | [
"Pedigree",
"for",
"Family",
"#2",
"(CRC:",
"Colorectal",
"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.",
"No",
"genetic",
"testing",
"was",
"available",
"from",
"the",
"father",
"or",
"paternal",
"relatives",
"(Family",
"#2,",
"Figure",
"3)."
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] | Pedigree for Family #2 (CRC: Colorectal 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. No genetic testing was available from the father or paternal relatives (Family #2, Figure 3). |
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",
"±",
"1.7",
"vs",
"0.8",
"±",
"1.0;",
"P",
"<",
"0.001).",
"Multivariate",
"analysis",
"revealed",
"that",
"MSI+",
"was",
"the",
"only",
"significant",
"independent",
"predictor",
"of",
"BRAF",
"mutation",
"(RR",
"=",
"6.3,",
"95%CI",
"[1.2–32.3];",
"P",
"=",
"0.028)",
"in",
"a",
"model",
"that",
"included",
"CIMP+,",
"tumor",
"site,",
"histological",
"grade,",
"presence",
"of",
"infiltrating",
"lymphocytes",
"and",
"mucinous",
"appearance."
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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 ± 1.7 vs 0.8 ± 1.0; P < 0.001). Multivariate analysis revealed that MSI+ was the only significant independent predictor of BRAF mutation (RR = 6.3, 95%CI [1.2–32.3]; P = 0.028) in a model that included CIMP+, tumor site, histological grade, presence of infiltrating lymphocytes and mucinous appearance. |
2275286-04-Results-p02 | [
"Details",
"of",
"the",
"8",
"patients",
"in",
"MSS",
"group",
"identified",
"to",
"have",
"MMR",
"gene",
"germline",
"mutation"
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Details of the 8 patients in MSS group identified to have MMR gene germline mutation |
3034663-04-Results-p02 | [
"Of",
"the",
"17",
" ",
"CRC",
"patients",
"with",
"the",
"Lys618Ala",
"variant,",
"two",
" ",
"had",
"MSI",
"(11.8%),",
"one",
"in",
"the",
"familial",
"CRC",
"group",
"(",
"1/8",
")",
"and",
"one",
"in",
"the",
"sporadic",
"CRC",
"group",
"(1/9)."
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] | Of the 17 CRC patients with the Lys618Ala variant, two had MSI (11.8%), one in the familial CRC group ( 1/8 ) and one in the sporadic CRC group (1/9). |
1619718-03-Materials-and-methods-p02 | [
"This",
"was",
"undertaken",
"on",
"all",
"adenomas",
"and",
"all",
"serrated",
"polyps",
"with",
"dysplasia",
"(traditional",
"SA",
"and",
"MP",
").",
"Most",
"of",
"these",
"polyps",
"had",
"been",
"immunostained",
"previously",
"for",
"MGMT.24",
"Following",
"deparaffinization",
"and",
"rehydration",
"of",
"4-µm",
"sections",
"and",
"antigen",
"retrieval",
"using",
"ethylene",
"diamine",
"tetra-acetic",
"acid",
"and",
"microwaving,",
"the",
"sections",
"were",
"subjected",
"to",
"peroxidase",
"blockade",
"(Dako",
"EnVision",
"bottle",
"1;",
"Mississauga,",
"Canada)",
"and",
"then",
"incubated",
"in",
"10%",
"goat",
"serum",
"to",
"minimize",
"non-specific",
"staining.",
"They",
"were",
"subsequently",
"incubated",
"with",
"the",
"primary",
"anti-p53",
"antibody",
"(DO-7,",
"from",
"DakoCytomation,",
"Mississauga,",
"Canada)",
"at",
"a",
"dilution",
"of",
"1",
":",
"100",
"for",
"60",
"min",
"at",
"37°C.",
"After",
"washing,",
"the",
"sections",
"were",
"incubated",
"with",
"secondary",
"antibody",
"(EnVision",
"bottle",
"2)",
"for",
"30",
"min,",
"washed",
"again",
"and",
"then",
"developed",
"with",
"the",
"chromogen",
"AEC",
"for",
"30",
"min.",
"Finally,",
"the",
"sections",
"were",
"counterstained",
"with",
"Gill's",
"haematoxylin.",
"Polyps",
" ",
"were",
"scored",
"as",
"showing",
"loss",
"of",
"expression",
"of",
"MGMT",
"normal",
" ",
"mucosa)",
"and",
"180",
"µl",
"of",
"ATL",
"buffer",
"were",
"dissolved",
"at",
"80°C",
"and",
"then",
"digested",
"overnight",
"with",
"20",
"µl",
"of",
"proteinase",
"K",
"at",
"55°C.",
"Following",
"centrifugation",
"at",
"2000",
"r.p.m.",
"(300",
"g)",
"for",
"5",
"min,",
"the",
"lower",
"phase",
"was",
"applied",
"to",
"a",
"DNeasy",
"tissue",
"column.",
"Bound",
"DNA",
"was",
"washed",
"by",
"centrifugation",
"through",
"ethanol",
"and",
"then",
"eluted",
"from",
"the",
"column",
"using",
"AE",
"buffer."
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] | This was undertaken on all adenomas and all serrated polyps with dysplasia (traditional SA and MP ). Most of these polyps had been immunostained previously for MGMT.24 Following deparaffinization and rehydration of 4-µm sections and antigen retrieval using ethylene diamine tetra-acetic acid and microwaving, the sections were subjected to peroxidase blockade (Dako EnVision bottle 1; Mississauga, Canada) and then incubated in 10% goat serum to minimize non-specific staining. They were subsequently incubated with the primary anti-p53 antibody (DO-7, from DakoCytomation, Mississauga, Canada) at a dilution of 1 : 100 for 60 min at 37°C. After washing, the sections were incubated with secondary antibody (EnVision bottle 2) for 30 min, washed again and then developed with the chromogen AEC for 30 min. Finally, the sections were counterstained with Gill's haematoxylin. Polyps were scored as showing loss of expression of MGMT normal mucosa) and 180 µl of ATL buffer were dissolved at 80°C and then digested overnight with 20 µl of proteinase K at 55°C. Following centrifugation at 2000 r.p.m. (300 g) for 5 min, the lower phase was applied to a DNeasy tissue column. Bound DNA was washed by centrifugation through ethanol and then eluted from the column using AE buffer. |
1557864-03-Methods-p01 | [
"DNA",
"isolation:",
"microsatellite",
"analysis",
"and",
"methylation",
"specific",
"PCR"
] | [
0,
0,
0,
0,
0,
0,
0,
0
] | DNA isolation: microsatellite analysis and methylation specific PCR |
1557864-01-Abstract-p01 | [
"Seven",
"of",
"the",
"75",
"no",
"altered",
"expression",
"of",
"MMR",
"genes",
"2774",
" ",
"(no",
"altered",
"expression",
"of",
"MMR",
"genes).",
"Overall,",
"there",
"was",
"no",
"association",
"between",
"cisplatin",
"response",
"and",
"MMR",
"status",
"in",
"these",
"eight",
"cell",
"lines."
] | [
11,
12,
12,
12,
7,
8,
8,
8,
8,
8,
9,
0,
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] | Seven of the 75 no altered expression of MMR genes 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. |
1266026-05-Discussion-p02 | [
"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",
"colon.",
"Early",
"or",
"advanced",
"sporadic",
"MSI-",
"colorectal",
"cancers",
"appeared",
"to",
"require",
"similar",
"numbers",
"of",
"mutations,",
"consistent",
"with",
"the",
"phenotype",
"at",
"cancer",
"diagnosis",
"contingent",
"on",
"mutations",
"acquired",
"much",
"earlier",
"in",
"life",
"and",
"present",
"at",
"the",
"time",
"of",
"transformation.",
"However,",
"ascertainment",
"bias",
"may",
"also",
"be",
"responsible",
"for",
"the",
"similar",
"frequency-age",
"distributions",
"of",
"colorectal",
"cancers",
"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]."
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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 colon. Early or advanced sporadic MSI- colorectal cancers appeared to require similar numbers of mutations, consistent with the phenotype at cancer diagnosis contingent on mutations acquired much earlier in life and present at the time of transformation. However, ascertainment bias may also be responsible for the similar frequency-age distributions of colorectal cancers 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]. |
3034663-04-Results-p01 | [
"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)."
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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). |
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,",
"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, 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]. |
1619718-01-Abstract-p01 | [
"Thirty-two",
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"adenomas",
"(SSA),",
"10",
"mixed",
"polyps",
"(MP),",
"15",
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"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%",
"MGMT",
"SSA",
"sessile",
" ",
"serrated",
" ",
"adenomas",
"polyps",
"colorectal",
"colorectal",
"polyps",
" ",
"and",
"adenomas:",
"concept",
"of",
"a",
"‘fusion’",
"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% MGMT SSA sessile serrated adenomas polyps colorectal colorectal polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancer |
2275286-02-Background-p01 | [
"MSI",
"is",
"an",
"important",
"phenotype",
"of",
"MMR",
"gene",
"mutation.",
"In",
"1997,",
"the",
"National",
"Cancer",
"Institute",
"(NCI)",
"recommended",
"screening",
"MSI",
"CRCs",
"using",
"the",
"Bethesda",
"guidelines",
"[5].",
"After",
"compiling",
"evidence",
"from",
"years",
"of",
"global",
"studies",
"and",
"follow",
"up,",
"NCI",
"revised",
"the",
"Bethesda",
"guidelines",
"in",
"2004,",
"which",
"is",
"called",
"the",
"revised",
"Bethesda",
"standard",
"[6].",
"NCI",
"recommended",
"screening",
"of",
"HNPCC",
"based",
"on",
"detection",
"of",
"MSI",
"in",
"the",
"tumor",
"and",
"loss",
"of",
"expression",
"of",
"a",
"MMR",
"gene",
"using",
"immunohistochemistry",
"(IHC)",
"staining",
"[6].",
"However,",
"until",
"now,",
"there",
"has",
"been",
"no",
"research",
"about",
"the",
"applicability",
"of",
"the",
"NCI",
"recommendations",
"to",
"the",
"Chinese",
"population",
"with",
"colorectal",
"cancers.",
"The",
"aim",
"of",
"this",
"study",
"is",
"to",
"detect",
"and",
"study",
"MSI",
"carrier",
"colorectal",
"cancer",
"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. In 1997, the National Cancer Institute (NCI) recommended screening MSI CRCs using the Bethesda guidelines [5]. After compiling evidence from years of global studies and follow up, NCI revised the Bethesda guidelines in 2004, which is called the revised Bethesda standard [6]. NCI recommended screening of HNPCC based on detection of MSI in the tumor and loss of expression of a MMR gene using immunohistochemistry (IHC) staining [6]. However, until now, there has been no research about the applicability of the NCI recommendations to the Chinese population with colorectal cancers. The aim of this study is to detect and study MSI carrier colorectal cancer 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. |
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",
"did",
"not",
"respond",
"to",
"cisplatin/paclitaxel",
"therapy.",
"So",
"the",
"resistance",
"seen",
"in",
"these",
"seven",
"nonresponding",
"patients",
"eleven",
" ",
"did",
"not",
"respond",
"and",
"34",
"did.",
"For",
"one",
"patient",
"the",
"response",
"was",
"not",
"known.",
"Methylation",
"of",
"the",
"MLH1",
"promoter",
"carcinomas",
"carcinomas",
" ",
"we",
"analyzed",
"had",
"been",
"treated",
"with",
"platinum-based",
"chemotherapy,",
"eleven",
"did",
"not",
"respond",
"and",
"34",
"did.",
"For",
"one",
"patient",
"the",
"response",
"was",
"not",
"known.",
"Methylation",
"of",
"the",
"MLH1",
"promoter",
"was",
"detected",
"in",
"two",
"of",
"the",
"eleven",
"non-responders",
"(18%)",
"and",
"four",
"of",
"the",
"34",
"responders",
"(12%)",
"and",
"this",
"was",
"not",
"significantly",
"different",
"(p",
"=",
"0.664).",
"Since",
"we",
"did",
"not",
"detect",
"any",
"MSI,",
"the",
"resistance",
"seen",
"in",
"the",
"eleven",
"patients",
"could",
"not",
"be",
"associated",
"with",
"MSI",
"and",
"MMR",
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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 did not respond to cisplatin/paclitaxel therapy. So the resistance seen in these seven nonresponding patients eleven did not respond and 34 did. For one patient the response was not known. Methylation of the MLH1 promoter carcinomas carcinomas we analyzed had been treated with platinum-based chemotherapy, eleven did not respond and 34 did. For one patient the response was not known. Methylation of the MLH1 promoter was detected in two of the eleven non-responders (18%) and four of the 34 responders (12%) and this was not significantly different (p = 0.664). Since we did not detect any MSI, the resistance seen in the eleven patients could not be associated with MSI and MMR inactivation. |
1334229-01-Abstract-p01 | [
"The",
"early",
"to",
"intermediate",
"stages",
"of",
"the",
"majority",
"of",
"colorectal",
"tumours",
"are",
"thought",
"to",
"be",
"driven",
"by",
"aberrations",
"in",
"the",
"Wnt",
"(APC,",
"CTNNB1)",
"and",
"Ras",
"(K-ras)",
"pathways.",
"A",
"smaller",
"proportion",
"of",
"cancers",
"shows",
"mismatch",
"repair",
"deficiency.",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"analyse",
"the",
"co-occurrence",
"of",
"these",
"genetic",
"alterations",
"in",
"relation",
"to",
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] | The early to intermediate stages of the majority of colorectal tumours are thought to be driven by aberrations in the Wnt (APC, CTNNB1) and Ras (K-ras) pathways. A smaller proportion of cancers shows mismatch repair deficiency. The aim of this study was to analyse the co-occurrence of these genetic alterations in relation to tumour and patient characteristics. |
2386495-01-Abstract-p01 | [
"**",
"IGNORE",
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0,
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1373649-02-Background-p01 | [
"Since",
"there",
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"susceptibility",
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"HNPCC,",
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"the",
"primary",
"method",
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"identifying",
"patients",
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"(referred",
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"as",
"the",
"Amsterdam-I",
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"[3]):",
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"or",
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"histologically",
"verified",
"colorectal",
"cancer,",
"one",
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"whom",
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"a",
"first-degree",
"relative",
"of",
"the",
"other",
"two;",
"2.",
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"cancer",
"affecting",
"at",
"least",
"2",
"successive",
"generations;",
"and",
"3.",
"At",
"least",
"one",
"relative",
"diagnosed",
"with",
"colorectal",
"cancer",
"under",
"the",
"age",
"of",
"50.",
"The",
"fulfillment",
"of",
"these",
"criteria",
"prompted",
"further",
"genetics",
"investigations.",
"More",
"recently",
"it",
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"been",
"revised",
"to",
"take",
"into",
"account",
"the",
"prevalence",
"of",
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] | Since there are no premonitory signs of susceptibility to HNPCC, family history has been the primary method for identifying patients at risk. Defined by the International Collaborative group on HNPCC, the typical HNPCC family fulfill the following criteria (referred to as the Amsterdam-I criteria [3]): 1. Three or more relatives with histologically verified colorectal cancer, one of whom is a first-degree relative of the other two; 2. Colorectal cancer affecting at least 2 successive generations; and 3. At least one relative diagnosed with colorectal cancer under the age of 50. The fulfillment of these criteria prompted further genetics investigations. More recently it has been revised to take into account the prevalence of extracolonic cancer in certain HNPCC families [4]. |
3034663-04-Results-p01 | [
"There",
"were",
"no",
"significant",
"associations",
"in",
"the",
"case-control",
"and",
"case-case",
"studies",
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"power,",
"OR",
"=",
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"two-sided",
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] | There were no significant associations in the case-control and case-case studies (80% detection power, OR = 3.0; two-sided test, alpha level = 5%) (Table 2) and no statistically significant associations when the OR was adjusted for age and sex. |
3034663-03-Methods-p01 | [
"Concomitant",
"deleterious",
"variants",
"were",
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"the",
"families:",
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"(c.3013C>T;",
"p.Arg1005X).",
"Seventeen",
"affected",
"and",
"unaffected",
"family",
"members",
"from",
"these",
"two",
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"were",
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"for",
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"and",
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] | Concomitant deleterious variants were detected in two of the families: one in the MLH1 gene (c.676C>T; p.Arg226X) and the other in the MSH6 gene (c.3013C>T; p.Arg1005X). Seventeen affected and unaffected family members from these two families were tested for the pathogenic and p.Lys618Ala variants. |
1266026-05-Discussion-p02 | [
"Equivalent",
"numbers",
"of",
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"regardless",
"of",
"clinical",
"stage",
"are",
"consistent",
"with",
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"an",
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"[22],",
"albeit",
"only",
"rare",
"cells",
"actually",
"form",
"visible",
"metastases.",
"Primary",
"breast",
" ",
"cancer",
"expression",
"patterns",
"correlate",
"with",
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"or",
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"[22-25],",
"suggesting",
"that",
"a",
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"time",
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"surveillance",
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] | Equivalent numbers of mutations regardless of clinical stage are consistent with recent speculation that an invasive potential is acquired early in progression [22], albeit only rare cells actually form visible metastases. Primary breast cancer expression patterns correlate with clinical outcomes or metastases [22-25], suggesting that a propensity to spread is already present at the time of transformation. Alternatively, all cancers may have the same abilities to invade and metastasize, with clinical stage dependent on random events that occur rapidly after transformation. A short interval between transformation and detection may help limit spread because clinical surveillance tends to detect localized colorectal cancers [26-28]. |
2386495-05-Discussion-p04 | [
"Mutation-detection",
"frequency"
] | [
0,
0
] | Mutation-detection frequency |
2386495-03-Methods-p01 | [
"Patient",
"C896,",
"with",
"only",
"five",
"adenomas,",
"was",
"included",
"because",
"of",
"a",
"family",
"history",
"of",
"FAP.",
"Patient",
"C107",
"underwent",
"her",
"first",
"colonoscopy",
"due",
"to",
"intestinal",
"bleeding",
"at",
"age",
"47.",
"At",
"diagnosis,",
"10–20",
"small",
"(less",
"than",
"10",
"mm)",
"polyps",
"were",
"found",
"in",
"most",
"colorectal",
"parts.",
"Tubular",
"and",
"tubulovillous",
"adenomas",
"were",
"removed",
"yearly.",
"At",
"age",
"50",
"age",
"47",
"Patient",
"FGP",
",",
"fundic",
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"polyps;",
"NA,",
"no",
"available",
"data;",
"NI,",
"no",
"inheritance;",
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"of",
"polyps,",
"number",
"of",
"polyps",
"at",
"diagnosis;",
"rec,",
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] | Patient C896, with only five adenomas, was included because of a family history of FAP. Patient C107 underwent her first colonoscopy due to intestinal bleeding at age 47. At diagnosis, 10–20 small (less than 10 mm) polyps were found in most colorectal parts. Tubular and tubulovillous adenomas were removed yearly. At age 50 age 47 Patient FGP , fundic gland polyps; NA, no available data; NI, no inheritance; Number of polyps, number of polyps at diagnosis; rec, recessive |
3034663-04-Results-p01 | [
"Pedigree",
"for",
"Family",
"#1",
"(CRC:",
"Colorectal",
"cancer;",
"GC:",
"Gastric",
"cancer;",
"DC:",
"Duodenal",
"cancer)."
] | [
0,
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0,
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0,
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0,
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] | Pedigree for Family #1 (CRC: Colorectal cancer; GC: Gastric cancer; DC: Duodenal cancer). |
1601966-03-Results-p08 | [
"Down-regulation",
"of",
"mRNA",
"expression",
"in",
"human",
"chromosomal",
"region",
"1p36.13-1p36.11",
"(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.",
"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",
"10.",
"This",
"region",
"has",
"been",
"reported",
"in",
"other",
"studies",
"to",
"be",
"frequently",
"deleted",
"in",
"colorectal",
"cancer",
"(see",
"Table",
"4).",
"This",
"is",
"the",
"most",
"significantly",
"down-regulated",
"region",
"of",
"our",
"analysis.",
"Note",
"the",
"expression",
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"potential",
"tumor",
"genes",
"PLA2G2A,",
"E2F2,",
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] | Down-regulation of mRNA expression in human chromosomal region 1p36.13-1p36.11 (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. 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 10. This region has been reported in other studies to be frequently deleted in colorectal cancer (see Table 4). This is the most significantly down-regulated region of our analysis. Note the expression of potential tumor genes PLA2G2A, E2F2, and CDC42. |
1619718-04-Results-p03 | [
"Aberrant",
"expression",
"of",
"p53",
"and",
"correlation",
"with",
"MGMT",
"loss"
] | [
0,
0,
0,
0,
0,
0,
0,
0,
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] | Aberrant expression of p53 and correlation with MGMT loss |
1619718-01-Abstract-p01 | [
"To",
"establish",
"and",
"explain",
"the",
"pattern",
"of",
"molecular",
"signatures",
"across",
"colorectal",
"polyps."
] | [
0,
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0,
0,
0,
0,
0,
0,
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] | To establish and explain the pattern of molecular signatures across colorectal polyps. |
2386495-04-Results-p03 | [
"Splice-site",
"affecting",
"mutations"
] | [
0,
0,
0
] | Splice-site affecting mutations |
2275286-01-Abstract-p01 | [
"Hereditary",
"nonpolyposis",
"colorectal",
"cancer",
"(HNPCC)",
"is",
"an",
"autosomal",
"dominant",
"syndrome.",
"The",
"National",
"Cancer",
"Institute",
"(NCI)",
"has",
"recommended",
"the",
"Revised",
"Bethesda",
"guidelines",
"for",
"screening",
"HNPCC.",
"There",
"has",
"been",
"a",
"great",
"deal",
"of",
"research",
"on",
"the",
"value",
"of",
"these",
"tests",
"in",
"other",
"countries.",
"However,",
"literature",
"about",
"the",
"Chinese",
"population",
"is",
"scarce.",
"Our",
"objective",
"is",
"to",
"detect",
"and",
"study",
"microsatellite",
"instability",
"(MSI)",
"and",
"mismatch",
"repair",
"(MMR)",
"gene",
"germline",
"mutation",
"carriers",
"among",
"a",
"Chinese",
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1601966-03-Results-p03 | [
"Individual",
"chromosomal",
"islands",
"of",
"up-",
"or",
"down-regulation."
] | [
0,
0,
0,
0,
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] | Individual chromosomal islands of up- or down-regulation. |
1619718-03-Materials-and-methods-p02 | [
"**",
"IGNORE",
"LINE",
"**"
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0,
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] | ** IGNORE LINE ** |