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1334229-04-Results-p02 | [
"Next,",
"we",
"compared",
"the",
"patient",
"and",
"tumour",
"characteristics",
"of",
"tumours",
"harbouring",
"a",
"truncating",
"APC",
"and/or",
"an",
"activating",
"K-ras",
"mutation",
"to",
"those",
"of",
"tumours",
"without",
"hMLH1",
"expression,",
"and",
"these",
"results",
"are",
"presented",
"in",
"table",
"4.",
"Patients",
"harbouring",
"hMLH1",
"deficient",
"tumours",
"were",
"slightly",
"older",
"when",
"diagnosed",
"with",
"colorectal",
"cancer",
"(69.3",
"yr",
"(68.0–70.5)",
"versus",
"67.8",
"(67.4–68.3),",
"P",
"=",
"0.03),",
"were",
"relatively",
"less",
"frequently",
"men",
"(40%",
"versus",
"58%",
"rectosigmoid",
" ",
"and",
"rectum",
"more",
"frequently",
"harboured",
"truncating",
"APC",
"mutations",
"when",
"compared",
"to",
"colon",
"tumours",
"(P",
"=",
"0.001),",
"as",
"shown",
"in",
"table",
"3.",
"Rectosigmoid",
"and",
"rectal",
"tumours",
"have",
"a",
"relatively",
"higher",
"frequency",
"of",
"K-ras",
"mutations",
"in",
"codons",
"12",
"and",
"13",
"when",
"compared",
"to",
"colon",
"tumours",
"(P",
"=",
"0.05)",
"(Table",
"3).",
"Nine",
"per",
"cent",
"of",
"tumours",
"showed",
"hMLH1",
"deficiency,",
"as",
"determined",
"by",
"immunohistochemistry",
"(Figure",
"2).",
"Tumours",
"lacking",
"hMLH1",
"expression",
"occur",
"almost",
"exclusively",
"in",
"the",
"proximal",
"colon",
"(P",
"<",
"0.001)",
"and",
"relatively",
"more",
"frequently",
"show",
"poor",
"differentiation",
"or",
"are",
"undifferentiated",
"(P",
"<",
"0.001)",
"when",
"compared",
"to",
"tumours",
"with",
"hMLH1",
"expression",
"(Table",
"3)."
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] | Next, we compared the patient and tumour characteristics of tumours harbouring a truncating APC and/or an activating K-ras mutation to those of tumours without hMLH1 expression, and these results are presented in table 4. Patients harbouring hMLH1 deficient tumours were slightly older when diagnosed with colorectal cancer (69.3 yr (68.0–70.5) versus 67.8 (67.4–68.3), P = 0.03), were relatively less frequently men (40% versus 58% rectosigmoid and rectum more frequently harboured truncating APC mutations when compared to colon tumours (P = 0.001), as shown in table 3. Rectosigmoid and rectal tumours have a relatively higher frequency of K-ras mutations in codons 12 and 13 when compared to colon tumours (P = 0.05) (Table 3). Nine per cent of tumours showed hMLH1 deficiency, as determined by immunohistochemistry (Figure 2). Tumours lacking hMLH1 expression occur almost exclusively in the proximal colon (P < 0.001) and relatively more frequently show poor differentiation or are undifferentiated (P < 0.001) when compared to tumours with hMLH1 expression (Table 3). |
1619718-05-Discussion-p02 | [
"Serrated",
"polyps",
"with",
"dysplasia,",
"i.e.",
"MPs",
"and",
"SAs,",
"together",
"comprised",
"only",
"2%",
"of",
"the",
"overall",
"consecutive",
"series",
"of",
"1250",
"polyps.",
"While",
"mutation",
"of",
"KRAS",
"and",
"BRAF",
"was",
"associated",
"with",
"conventional",
"adenoma",
"and",
"SSA,",
"respectively",
"(see",
"above),",
"BRAF",
"and",
"KRAS",
"mutation",
"occurred",
"with",
"similar",
"frequency",
"in",
"both",
"MPs",
"(40%",
"and",
"50%,",
"respectively)",
"and",
"SAs",
"(33%",
"and",
"27%,",
"respectively).",
"In",
"the",
"literature,",
"the",
"frequency",
"of",
"BRAF",
"and",
"KRAS",
"mutation",
"in",
"MP",
"SSAs",
" ",
"(81%).",
"Previous",
"reports",
"have",
"shown",
"very",
"similar",
"results",
"for",
"BRAF",
"mutation",
"in",
"SSA,16",
"but",
"higher",
"frequencies",
"of",
"KRAS",
"mutation",
"and",
"lower",
"frequencies",
"of",
"BRAF",
"mutation",
"KRAS",
"SSA",
",16",
"but",
"higher",
"frequencies",
"of",
"KRAS",
"mutation",
"and",
"lower",
"frequencies",
"of",
"BRAF",
"mutation",
"in",
"HPs.12,16,38",
"As",
"mentioned",
"in",
"Materials",
"and",
"methods,",
"there",
"had",
"been",
"selection",
"of",
"larger",
"HPs",
"in",
"an",
"earlier",
"cell",
"kinetic",
"study",
"involving",
"the",
"same",
"material.",
"Large",
"HPs",
"are",
"more",
"likely",
"to",
"include",
"the",
"subset",
"described",
"as",
"‘microvesicular’,",
"in",
"which",
"the",
"columnar",
"cells",
"contain",
"apical",
"mucin",
"droplets",
"within",
"small",
"vesicles",
"while",
"goblet",
"cells",
"are",
"rendered",
"inconspicuous.25BRAF",
"mutation",
"occurs",
"more",
"frequently",
"in",
"the",
"microvesicular",
"variant",
"of",
"HP.16",
"By",
"contrast,",
"KRAS",
"mutation",
"occurs",
"much",
"more",
"commonly",
"in",
"the",
"goblet",
"cell",
"variant",
"of",
"HP,",
"which",
"is",
"usually",
"small,",
"located",
"in",
"the",
"left",
"colon",
"or",
"rectum",
"and",
"deviates",
"minimally",
"from",
"normal",
"colorectal",
"mucosa",
"in",
"terms",
"of",
"differentiation",
"and",
"architecture.16,25",
"The",
"latter",
"were",
"under-represented",
"in",
"this",
"series",
"(details",
"not",
"shown)."
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] | Serrated polyps with dysplasia, i.e. MPs and SAs, together comprised only 2% of the overall consecutive series of 1250 polyps. While mutation of KRAS and BRAF was associated with conventional adenoma and SSA, respectively (see above), BRAF and KRAS mutation occurred with similar frequency in both MPs (40% and 50%, respectively) and SAs (33% and 27%, respectively). In the literature, the frequency of BRAF and KRAS mutation in MP SSAs (81%). Previous reports have shown very similar results for BRAF mutation in SSA,16 but higher frequencies of KRAS mutation and lower frequencies of BRAF mutation KRAS SSA ,16 but higher frequencies of KRAS mutation and lower frequencies of BRAF mutation in HPs.12,16,38 As mentioned in Materials and methods, there had been selection of larger HPs in an earlier cell kinetic study involving the same material. Large HPs are more likely to include the subset described as ‘microvesicular’, in which the columnar cells contain apical mucin droplets within small vesicles while goblet cells are rendered inconspicuous.25BRAF mutation occurs more frequently in the microvesicular variant of HP.16 By contrast, KRAS mutation occurs much more commonly in the goblet cell variant of HP, which is usually small, located in the left colon or rectum and deviates minimally from normal colorectal mucosa in terms of differentiation and architecture.16,25 The latter were under-represented in this series (details not shown). |
1373649-04-Results-and-discussion-p01 | [
"Evolutionary",
"conservation,",
"examined",
"by",
"alignment",
"of",
"sequences",
"of",
"homologous",
"proteins",
"for",
"several",
"species",
"(fig.",
"4),",
"suggests",
"a",
"functional",
"relevance",
"for",
"the",
"amino",
"acid",
"involved.",
"This",
"is",
"also",
"supported",
"by",
"the",
"mutator",
"phenotype",
"described",
"for",
"Pro640Leu",
"mother",
"hMLH1",
" ",
"genes",
"was",
"indicated,",
"detecting",
"a",
"novel",
"germline",
"mutation,",
"a",
"c.1864C>A",
"transversion",
"in",
"exon",
"12",
"of",
"hMSH2",
"hMSH2",
" ",
"and",
"hMLH1",
"genes",
"was",
"indicated,",
"detecting",
"a",
"novel",
"germline",
"mutation,",
"a",
"c.1864C>A",
"transversion",
"in",
"exon",
"12",
"of",
"hMSH2",
"gene",
"at",
"the",
"heterozygous",
"state",
"(fig.",
"3)",
"leading",
"to",
"a",
"proline",
"622",
"to",
"threonine",
"(p.Pro622Thr)",
"amino",
"acid",
"substitution.",
"This",
"is",
"the",
"second",
"report",
"involving",
"the",
"622",
"codon",
"in",
"HNPCC",
"[13]."
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] | Evolutionary conservation, examined by alignment of sequences of homologous proteins for several species (fig. 4), suggests a functional relevance for the amino acid involved. This is also supported by the mutator phenotype described for Pro640Leu mother hMLH1 genes was indicated, detecting a novel germline mutation, a c.1864C>A transversion in exon 12 of hMSH2 hMSH2 and hMLH1 genes was indicated, detecting a novel germline mutation, a c.1864C>A transversion in exon 12 of hMSH2 gene at the heterozygous state (fig. 3) leading to a proline 622 to threonine (p.Pro622Thr) amino acid substitution. This is the second report involving the 622 codon in HNPCC [13]. |
3034663-04-Results-p01 | [
"Results",
"of",
"genotyping",
"for",
"the",
"p.Lys618Ala",
"variant",
"using",
"the",
"iPLEX",
"Sequenom",
"(A)",
"and",
"sequencing",
"(B)",
"methods."
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] | Results of genotyping for the p.Lys618Ala variant using the iPLEX Sequenom (A) and sequencing (B) methods. |
1334229-01-Abstract-p01 | [
"In",
"a",
"group",
"of",
"656",
"unselected",
"sporadic",
"colorectal",
"cancer",
"patients,",
"aberrations",
"in",
"the",
"APC,",
"K-ras,",
"CTNNB1",
"genes,",
"and",
"expression",
"of",
"hMLH1",
"were",
"investigated.",
"Additionally,",
"tumours",
"were",
"divided",
"in",
"groups",
"based",
"on",
"molecular",
"features",
"and",
"compared",
"with",
"respect",
"to",
"patient's",
"age",
"at",
"diagnosis,",
"sex,",
"family",
"history",
"of",
"colorectal",
"cancer,",
"tumour",
"sub-localisation,",
"Dukes'",
"stage",
"and",
"differentiation."
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] | In a group of 656 unselected sporadic colorectal cancer patients, aberrations in the APC, K-ras, CTNNB1 genes, and expression of hMLH1 were investigated. Additionally, tumours were divided in groups based on molecular features and compared with respect to patient's age at diagnosis, sex, family history of colorectal cancer, tumour sub-localisation, Dukes' stage and differentiation. |
1619718-01-Abstract-p01 | [
"Aim"
] | [
0
] | Aim |
1334229-05-Discussion-p02 | [
"The",
"method",
"for",
"mutation",
"analysis",
"of",
"the",
"APC",
" ",
"mutation",
"cluster",
"region",
"and",
"exon",
"1",
"of",
"K-ras",
"is",
"based",
"on",
"nested",
"amplification",
"and",
"direct",
"sequencing",
"of",
"purified",
"PCR",
"fragments,",
"a",
"highly",
"sensitive",
"method.",
"Since",
"no",
"screening",
"step",
"was",
"performed",
"prior",
"to",
"the",
"sequencing",
"of",
"the",
"gene",
"fragments,",
"it",
"is",
"unlikely",
"that",
"mutations",
"would",
"have",
"escaped",
"detection.",
"The",
"reproducibility",
"of",
"the",
"applied",
"assays",
"was",
"good,",
"with",
"a",
"reproducibility",
"of",
"85%",
"and",
"88%",
"for",
"APC",
" ",
"and",
"K-ras,",
"respectively.",
"Arguably,",
"this",
"indicates",
"the",
"extent",
"of",
"heterogeneity",
"present",
"in",
"the",
"tumour",
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] | The method for mutation analysis of the APC mutation cluster region and exon 1 of K-ras is based on nested amplification and direct sequencing of purified PCR fragments, a highly sensitive method. Since no screening step was performed prior to the sequencing of the gene fragments, it is unlikely that mutations would have escaped detection. The reproducibility of the applied assays was good, with a reproducibility of 85% and 88% for APC and K-ras, respectively. Arguably, this indicates the extent of heterogeneity present in the tumour samples. |
1373649-02-Background-p01 | [
"**",
"IGNORE",
"LINE",
"**"
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1373649-04-Results-and-discussion-p01 | [
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"by",
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"his",
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"according",
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"rules",
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"any",
"other",
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0,
0,
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] | In the present case, we overcame the difficulty of having a proband post-mortem non-tumor tissue sample for MSI testing by studying the alleles carried by his progenitors. Microsatellites are inherited according to Mendelian rules like any other genetic markers. Each progenitor pass one of its two alleles to its offspring and by definition, the alleles present in the proband's tumor tissue but absent in his progenitors are the result of somatic mutation. |
3034663-04-Results-p01 | [
"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."
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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. |
1334229-05-Discussion-p01 | [
"In",
"this",
"study,",
"the",
"occurrence",
"of",
"mutations",
"in",
"the",
"APC,",
"CTNNB1",
"and",
"K-ras",
"genes",
"as",
"well",
"as",
"expression",
"of",
"the",
"hMLH1",
"protein",
"in",
"tumour",
"tissue",
"of",
"656",
"sporadic",
"colorectal",
"cancer",
"cases",
"were",
"investigated.",
"The",
"occurrence",
"of",
"mutations",
"in",
"the",
"CTNNB1",
"gene,",
"which",
"codes",
"for",
"β-catenin,",
"was",
"rare:",
"only",
"five",
"of",
"464",
"tumours",
"analysed",
"were",
"found",
"to",
"have",
"a",
"mutation",
"at",
"one",
"of",
"the",
"phosphorylation",
"sites",
"in",
"exon",
"3.",
"Truncating",
"mutations",
"in",
"APC",
"and",
"activating",
"mutations",
"in",
"K-ras",
"appeared",
"to",
"occur",
"at",
"similar",
"frequencies.",
"Although",
"tumours",
"harbouring",
"both",
"mutations",
"were",
"relatively",
"rare,",
"mutations",
"in",
"APC",
"and",
"K-ras",
"seemed",
"to",
"occur",
"co-dependently.",
"Nine",
"percent",
"of",
"all",
"tumours",
"(58/656)",
"lacked",
"hMLH1",
"expression,",
"and",
"in",
"these",
"tumours",
"almost",
"no",
"APC",
"or",
"K-ras",
"mutations",
"was",
"detected.",
"Patients",
"harbouring",
"a",
"tumour",
"with",
"absent",
"hMLH1",
"expression",
"were",
"older,",
"more",
"often",
"women,",
"more",
"often",
"had",
"proximal",
"colon",
"tumours",
"that",
"showed",
"poorer",
"differentiation",
"when",
"compared",
"to",
"patients",
"who",
"harboured",
"a",
"tumour",
"with",
"an",
"APC",
"and/or",
"K-ras",
"mutation."
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] | In this study, the occurrence of mutations in the APC, CTNNB1 and K-ras genes as well as expression of the hMLH1 protein in tumour tissue of 656 sporadic colorectal cancer cases were investigated. The occurrence of mutations in the CTNNB1 gene, which codes for β-catenin, was rare: only five of 464 tumours analysed were found to have a mutation at one of the phosphorylation sites in exon 3. Truncating mutations in APC and activating mutations in K-ras appeared to occur at similar frequencies. Although tumours harbouring both mutations were relatively rare, mutations in APC and K-ras seemed to occur co-dependently. Nine percent of all tumours (58/656) lacked hMLH1 expression, and in these tumours almost no APC or K-ras mutations was detected. Patients harbouring a tumour with absent hMLH1 expression were older, more often women, more often had proximal colon tumours that showed poorer differentiation when compared to patients who harboured a tumour with an APC and/or K-ras mutation. |
3034663-03-Methods-p01 | [
"DNA",
"from",
"blood",
"cells",
"(familial",
"cancer",
"cases",
"and",
"controls)",
"or",
"colorectal",
"mucosa",
"of",
"normal",
"appearance",
"(sporadic",
"cases)",
"was",
"used",
"for",
"the",
"c.1852_1853AA>GC",
"variant",
"genotyping.",
"This",
"was",
"assessed",
"using",
"the",
"iPLEX",
"Gold",
"method",
"(Sequenom,",
"CA,",
"USA),",
"in",
"which",
"single-base",
"extension",
"and",
"MALDI-TOF",
"technology",
"are",
"employed",
"for",
"allelic",
"discrimination.",
"These",
"experiments",
"were",
"carried",
"out",
"at",
"the",
"Centro",
"Español",
"de",
"Genotipado",
"(CEGEN)",
"genotyping",
"platform",
"facilities.",
"Quality",
"control",
"for",
"genotyping",
"was",
"conducted",
"by",
"direct",
"sequencing",
"of",
"familial",
"cancer",
"subjects",
"who",
"underwent",
"genetic",
"analysis",
"for",
"MLH1",
"(49/1034,",
"4.7%",
"CRC",
" ",
"cases"
] | [
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] | DNA from blood cells (familial cancer cases and controls) or colorectal mucosa of normal appearance (sporadic cases) was used for the c.1852_1853AA>GC variant genotyping. This was assessed using the iPLEX Gold method (Sequenom, CA, USA), in which single-base extension and MALDI-TOF technology are employed for allelic discrimination. These experiments were carried out at the Centro Español de Genotipado (CEGEN) genotyping platform facilities. Quality control for genotyping was conducted by direct sequencing of familial cancer subjects who underwent genetic analysis for MLH1 (49/1034, 4.7% CRC cases |
2275286-01-Abstract-p01 | [
"Conclusion"
] | [
0
] | Conclusion |
1266026-01-Abstract-p01 | [
"Methods"
] | [
0
] | Methods |
1334229-01-Abstract-p01 | [
"Conclusion"
] | [
0
] | Conclusion |
1557864-01-Abstract-p01 | [
"Results"
] | [
0
] | Results |
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",
"TA.",
"MGMT",
"immunstaining",
"not",
"performed",
"in",
"15",
"polyps",
"(seven",
"HPs,",
"one",
"SSA,",
"one",
"MP",
"and",
"six",
"TAs)."
] | [
0,
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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). |
1334229-03-Methods-p01 | [
"Tumour",
"material",
"of",
"colorectal",
"cancer",
"patients",
"was",
"collected",
"after",
"approval",
"by",
"the",
"Ethical",
"Review",
"Board",
"of",
"Maastricht",
"University,",
"PALGA",
"and",
"the",
"NCR.",
"Tissue",
"samples",
"from",
"819",
"colorectal",
"cancer",
"patients",
"were",
"localized",
"in",
"54",
"pathology",
"laboratories",
"throughout",
"the",
"Netherlands.",
"Forty-four",
"(5%)",
"tumour",
"tissue",
"samples",
" ",
"could",
"not",
"be",
"retrieved",
"from",
"the",
"pathology",
"archives.",
"Of",
"775",
"available",
"tissue",
"samples",
",",
"737",
"(95%)",
"contained",
"sufficient",
"tumour",
"material",
"for",
"molecular",
"analyses.",
"Tissue",
"sections",
"were",
"cut",
"from",
"each",
"sample,",
"which",
"were",
"used",
"for",
"DNA",
"isolation",
"and",
"immunohistochemical",
"analysis."
] | [
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] | Tumour material of colorectal cancer patients was collected after approval by the Ethical Review Board of Maastricht University, PALGA and the NCR. Tissue samples from 819 colorectal cancer patients were localized in 54 pathology laboratories throughout the Netherlands. Forty-four (5%) tumour tissue samples could not be retrieved from the pathology archives. Of 775 available tissue samples , 737 (95%) contained sufficient tumour material for molecular analyses. Tissue sections were cut from each sample, which were used for DNA isolation and immunohistochemical analysis. |
1266026-05-Discussion-p01 | [
"An",
"epigenetic",
"mechanism",
"may",
"help",
"explain",
"why",
"sporadic",
"MSI+",
"cancers",
"require",
"more",
"than",
"one",
"additional",
"somatic",
"alteration",
"relative",
"to",
"HNPCC",
"cancers.",
"Inactivation",
"of",
"the",
"normal",
"MMR",
"allele",
"occurs",
"through",
"mutation",
"(usually",
"LOH",
"[15])",
"in",
"HNPCC",
"whereas",
"MMR",
"loss",
"in",
"sporadic",
"MSI+",
"cancers",
"is",
"associated",
"with",
"MLH1",
"promoter",
"methylation",
"[16,17].",
"CpG",
"islands",
"may",
"be",
"\"protected\"",
"from",
"methylation",
"because",
"most",
"are",
"unmethylated",
"at",
"birth",
"and",
"usually",
"remain",
"unmethylated",
"throughout",
"life",
"[18].",
"Epigenetic",
"MLH1",
"inactivation",
"may",
"require",
"at",
"least",
"two",
"cis",
"acting",
"somatic",
"alterations---loss",
"of",
"a",
"mechanism",
"that",
"normally",
"prevents",
"methylation,",
"followed",
"by",
"the",
"accumulation",
"of",
"methylation",
"at",
"sufficient",
"numbers",
"of",
"CpG",
"sites",
"to",
"silence",
"expression."
] | [
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] | An epigenetic mechanism may help explain why sporadic MSI+ cancers require more than one additional somatic alteration relative to HNPCC cancers. Inactivation of the normal MMR allele occurs through mutation (usually LOH [15]) in HNPCC whereas MMR loss in sporadic MSI+ cancers is associated with MLH1 promoter methylation [16,17]. CpG islands may be "protected" from methylation because most are unmethylated at birth and usually remain unmethylated throughout life [18]. Epigenetic MLH1 inactivation may require at least two cis acting somatic alterations---loss of a mechanism that normally prevents methylation, followed by the accumulation of methylation at sufficient numbers of CpG sites to silence expression. |
1601966-03-Results-p03 | [
"Individual",
"chromosomal",
"islands",
"with",
"gain",
"of",
"expression"
] | [
0,
0,
0,
0,
0,
0,
0
] | Individual chromosomal islands with gain of expression |
1557864-01-Abstract-p01 | [
"No",
"MMR",
"inactivation",
"was",
"detected",
"in",
"75",
"ovarian",
"carcinoma",
"specimens",
"and",
"no",
"association",
"was",
"seen",
"between",
"MMR",
"inactivation",
"and",
"resistance",
"in",
"the",
"ovarian",
"cancer",
" ",
"cell",
"lines",
"as",
"well",
"as",
"the",
"ovarian",
"carcinomas.",
"In",
"the",
"discussion,",
"the",
"results",
"were",
"compared",
"to",
"that",
"of",
"twenty",
"similar",
"studies",
"in",
"the",
"literature",
"including",
"in",
"total",
"1315",
"ovarian",
"cancer",
"patients",
" ",
"received",
"platinum-based",
"chemotherapy",
"(11",
"non-responders,",
"34",
"responders,",
"one",
"unknown",
"response).",
"The",
"resistance",
"seen",
"in",
"the",
"eleven",
"non-responders",
"was",
"not",
"related",
"to",
"MSI",
"and",
"therefore",
"also",
"not",
"to",
"MMR",
"inactivation."
] | [
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] | No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. |
1266026-04-Results-p01 | [
"Mutation",
"number",
"estimates",
"with",
"respect",
"to",
"clinical",
"stage",
"may",
"be",
"biased",
"with",
"the",
"Finnish",
"data",
"because",
"it",
"includes",
"only",
"specimens",
"with",
"tissue",
"available",
"for",
"molecular",
"analysis.",
"Advanced",
"cancers",
"may",
"not",
"be",
"removed.",
"Therefore,",
"a",
"similar",
"analysis",
"was",
"performed",
"on",
"a",
"population-based",
"cancer",
"registry",
"[10]",
"from",
"the",
"United",
"States",
"of",
"America",
"(SEER",
"11",
"Regs",
"Public-Use,",
"Nov",
"2001",
"Sub",
"(1992–1999)),",
"which",
"records",
"ages",
"and",
"stages",
"at",
"diagnosis",
"regardless",
"of",
"treatment",
"(Table",
"2).",
"The",
"average",
"age",
"at",
"diagnosis",
"was",
"70.5",
"years,",
"consistent",
"with",
"an",
"estimate",
"of",
"six",
"mutations",
"to",
"colorectal",
"cancer",
"for",
"the",
"108,275",
"white",
"males",
"and",
"females",
"with",
"stage",
"data.",
"Like",
"the",
"Finnish",
"cancers",
"cancers",
" ",
"obtained",
"from",
"nine",
"large",
"regional",
"hospitals",
"in",
"southeastern",
"Finland",
"[9].",
"There",
"were",
"895",
"(87.6%)",
"MSI-",
"cancers",
"and",
"127",
"(12.4%)",
"MSI+",
"cancers.",
"The",
"MSI+",
"cancers",
"were",
"further",
"classified",
"as",
"sporadic",
"(N",
"=",
"98",
"or",
"9.6%",
"of",
"all",
"cancers)",
"or",
"HNPCC",
"(N",
"=",
"29",
"or",
"2.9%",
"of",
"all",
"cancers)",
"based",
"on",
"germline",
"MLH1",
"or",
"MSH2",
"mutations",
"(Table",
"1)."
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] | Mutation number estimates with respect to clinical stage may be biased with the Finnish data because it includes only specimens with tissue available for molecular analysis. Advanced cancers may not be removed. Therefore, a similar analysis was performed on a population-based cancer registry [10] from the United States of America (SEER 11 Regs Public-Use, Nov 2001 Sub (1992–1999)), which records ages and stages at diagnosis regardless of treatment (Table 2). The average age at diagnosis was 70.5 years, consistent with an estimate of six mutations to colorectal cancer for the 108,275 white males and females with stage data. Like the Finnish cancers cancers obtained from nine large regional hospitals in southeastern Finland [9]. There were 895 (87.6%) MSI- cancers and 127 (12.4%) MSI+ cancers. The MSI+ cancers were further classified as sporadic (N = 98 or 9.6% of all cancers) or HNPCC (N = 29 or 2.9% of all cancers) based on germline MLH1 or MSH2 mutations (Table 1). |
2386495-01-Abstract-p01 | [
"Using",
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"we",
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"a",
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"1250–1464,",
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] | Using a variety of mutation-detection techniques, we have achieved a 100% detection frequency in classical FAP. Probands with APC mutations outside codon 1250–1464, although exhibiting a less-severe phenotype, are at high risk of having a colorectal cancer at diagnosis indicating that age at diagnosis is as important as the severity of the disease for colorectal cancer cancer patients . |
3034663-03-Methods-p01 | [
"Concomitant",
"deleterious",
"variants",
"were",
"detected",
"in",
"two",
"of",
"the",
"families:",
"one",
"in",
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"gene",
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"p.Arg226X)",
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"other",
"in",
"the",
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"(c.3013C>T;",
"p.Arg1005X).",
"Seventeen",
"affected",
"and",
"unaffected",
"family",
"members",
"from",
"these",
"two",
"families",
"were",
"tested",
"for",
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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. |
1601966-03-Results-p04 | [
"20q11.22-q11.23"
] | [
0
] | 20q11.22-q11.23 |
1619718-04-Results-p01 | [
"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",
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"MGMT",
"loss",
"differs",
"across",
"the",
"seven",
"classes",
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"polyp",
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] | Mutation frequencies for both KRAS (P < 0.0001) and BRAF (P < 0.0001) are distributed differently across the seven classes of polyp (see Results for individual comparisons). Distribution of MGMT loss differs across the seven classes of polyp (P < 0.001). |
3034663-04-Results-p01 | [
"Pedigree",
"for",
"Family",
"#1",
"(CRC:",
"Colorectal",
"cancer;",
"GC:",
"Gastric",
"cancer;",
"DC",
":",
"Duodenal",
"nephews",
"nephews",
" ",
"(III-6;",
"III-7)",
"had",
"the",
"wild",
"types",
"of",
"the",
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"variants",
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"#1,",
"Figure",
"2)."
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] | Pedigree for Family #1 (CRC: Colorectal cancer; GC: Gastric cancer; DC : Duodenal nephews nephews (III-6; III-7) had the wild types of the two variants (Family #1, Figure 2). |
1557864-01-Abstract-p01 | [
"No",
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"inactivation",
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"in",
"75",
"ovarian",
"carcinoma",
"specimens",
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"inactivation",
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"cell",
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"ovarian",
" ",
"cancer",
"is",
"hindered",
"by",
"intrinsic",
"or",
"acquired",
"resistance",
"to",
"platinum-based",
"chemotherapy.",
"The",
"aim",
"of",
"this",
"study",
"is",
"to",
"determine",
"the",
"frequency",
"of",
"mismatch",
"repair",
"(MMR)",
"inactivation",
"in",
"ovarian",
" ",
"cancer",
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"its",
"association",
"with",
"resistance",
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] | No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. |
2275286-02-Background-p01 | [
"MSI",
"is",
"an",
"important",
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"mutation.",
"In",
"1997,",
"the",
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"Institute",
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"recommended",
"screening",
"MSI",
"CRCs",
"using",
"the",
"Bethesda",
"guidelines",
"[5].",
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"staining",
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"the",
"NCI",
"recommendations",
"to",
"the",
"Chinese",
"population",
"with",
"colorectal",
"cancers.",
"The",
"aim",
"of",
"this",
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"is",
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"detect",
"and",
"study",
"MSI",
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"and",
"mismatch",
"repair",
"Chinese",
" ",
"population",
"with",
"colorectal",
"cancers.",
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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 and mismatch repair Chinese population with colorectal cancers. The aim of this study is to detect and study MSI carrier and mismatch repair (MMR) gene germline mutation carriers among a Chinese germline mutation 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 and mismatch repair (MMR) gene germline mutation carriers among a Chinese population with colorectal cancer. |
1619718-05-Discussion-p03 | [
"Concept",
"of",
"‘fusion’",
"pathways",
"to",
"crc"
] | [
0,
0,
0,
0,
0,
0
] | Concept of ‘fusion’ pathways to crc |
1360090-03-Results-p01 | [
"Associations",
"between",
"BRAF",
"mutation",
"and",
"molecular",
"features",
"of",
"colorectal",
"cancer."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
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] | Associations between BRAF mutation and molecular features of colorectal cancer. |
1557864-06-Conclusion-p01 | [
"**",
"IGNORE",
"LINE",
"**"
] | [
0,
0,
0,
0
] | ** IGNORE LINE ** |
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 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. |
1619718-04-Results-p01 | [
"KRAS",
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1557864-01-Abstract-p01 | [
"Background"
] | [
0
] | Background |
3034663-04-Results-p01 | [
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3034663-05-Discussion-p01 | [
"Unfortunately,",
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3034663-05-Discussion-p01 | [
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1619718-04-Results-p01 | [
"Frequency",
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"BRAF",
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"loss",
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] | Frequency of KRAS and BRAF mutation and loss of expression of O-6-methylguanine DNA methyltransferase (MGMT) by polyp type |
2386495-04-Results-p02 | [
"**",
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1601966-03-Results-p11 | [
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] | The chromosomal region 14q24.3 has been implicated in colorectal patients patient counts with coordinate up-regulation). Grayscale cross-comparison plot of up-regulation patterns across patients (analogous to Figures 7, 10, 13). View this plot in conjunction with Figures 27 and 29. |
1334229-03-Methods-p03 | [
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] | The χ2 test and Cramérs V test were used to estimate the association of the co-occurrence of K-ras and APC gene mutations. Characteristics of patients (age at diagnosis, sex, family history of colorectal cancer hMLH1 tumours hMLH1 expression could be determined in 724 of 737 patients. |
1360090-03-Results-p01 | [
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2386495-04-Results-p02 | [
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1334229-03-Methods-p03 | [
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2386495-05-Discussion-p03 | [
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] | Screening for mosaic mutations in the three APC- and MUTYH-negative patients with de novo mutations revealed the c.2700_2701delTC mutation in 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. |
1619718-01-Abstract-p01 | [
"Molecular",
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"of",
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] | Molecular alterations that are characteristic of the serrated pathway and adenoma–carcinoma sequence can co-occur in a minority of advanced colorectal polyps that then show morphological features of both pathways. These lesions account for only 2% of colorectal serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancer |
1360090-04-Discussion-p01 | [
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1334229-01-Abstract-p01 | [
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1619718-05-Discussion-p04 | [
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] | Loss of expression of the DNA repair gene MGMT is associated with methylation of the promoter region45,51,52 and the latter change has been linked causatively with G:C to A:T transition mutations in TP53.53 In the present study, complete or partial loss of expression of MGMT coincided with aberrant nuclear expression of p53 in three serrated polyps with dysplasia (Figure 2), but not in the single tubular adenoma with aberrant p53 expression. Only one previous study has attempted to correlate MGMT and p53 expression in colorectal polyps.45 In that study, 4.3% of adenomas showed aberrant p53 expression but none had loss of MGMT. It is possible that the link between MGMT silencing and TP53 mutation is more evident in the serrated pathway than in the adenoma–carcinoma sequence. The frequency of TP53 mutation in SAs has ranged from 5 to 50% in the literature.39,41,54 Although a link between MGMT loss and aberrant expression of p53 is supported by the present findings, it should be noted that only a small number of polyps showed these changes concurrently. |
1619718-04-Results-p03 | [
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1601966-06-Methods-p05 | [
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2386495-04-Results-p03 | [
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] | The APC mutation in patient C633 was also detected by RNA-based PTT, followed by cDNA sequencing and genomic sequencing of APC exon 7 (Figure 4). The c.834G > C mutation changes the normal splice donor site of exon 7. This substitution reduces the score for usage of the wild-type splice donor site according to [37]. An alternative cryptic splice donor site 11 bp upstream in exon 7 is used in the mutant allele, leading to the aberrant splicing of exon 7. The resulting APC mRNA carries a frameshift, caused by the 11-bp deletion in the 3' end of exon 7, which leads to the premature truncation of the protein in exon 8. A third novel mutation affecting splicing frameshift, caused by the 11-bp deletion in the 3' end of exon 7, which leads to the premature truncation of the protein in exon 8 APC aberrant splicing of exon 7 . The resulting APC mRNA carries a frameshift, caused by the 11-bp deletion in the 3' end of exon 7, which leads to the premature truncation of the protein in exon 8. A third novel mutation affecting splicing of the APC c.834G > C C633 mutation c.835-7T > G C496 new AG splice-acceptor site eight bases upstream of exon 8 c.835-7T > G mutation (Figure 3A). The base substitution introduces a new AG splice-acceptor site eight bases upstream of exon 8. Owing to the use of this new splice site the last six bases of intron 7 are included in the transcript, resulting in premature truncation (Figure 3B). The entire APC coding region of the patient was sequenced and no other pathogenic variants were detected. A search for deletion or duplication of one or more exon in the APC gene by MLPA was also carried out with negative result. |
1619718-05-Discussion-p03 | [
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"independent",
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] | Colorectal polyps have traditionally been classified into distinct histogenetic types that may progress to CRC through independent pathways of colorectal tumorigenesis (Table 2). However, in addition to the two ‘classical’ pathways to CRC shown in Table 2, there may be ‘fusion’ pathways that combine mechanisms associated with both adenomas and serrated polyps. This would explain why many CRCs display phenotypes associated with serrated polyps as well as adenomas.44 Three possible examples of such fusion pathways are shown in Table 3. It is difficult to observe directly the actual point of transition from benign to malignant colorectal lesions. Once the key rate-limiting step is achieved it is likely that the transition to cancer occurs rapidly and the precursor lesion is then overtaken by the malignancy. Changes leading to inactivation of either TP535 or the DNA mismatch repair gene MLH113 are likely to be two such rate-limiting mechanisms. Only a single instance of loss of expression of MLH1 was observed in the present series of polyps and the adenoma in question was inferred to be from a patient with Lynch syndrome.24 |
2275286-04-Results-p02 | [
"*Statistical",
"analysis",
"was",
"made",
"between",
"MSI",
"and",
"MSS",
"group",
"only"
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | *Statistical analysis was made between MSI and MSS group only |
1619718-04-Results-p01 | [
"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)."
] | [
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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). |
1619718-05-Discussion-p04 | [
"MGMT",
"inactivation",
"predisposes",
"to",
"G:T",
"mismatches",
"and",
"chromosomal",
"instability",
"through",
"futile",
"cycles",
"of",
"excision",
"and",
"repair",
"as",
"well",
"as",
"to",
"mutation",
"of",
"KRAS",
"and",
"TP53.9",
"Partial",
"methylation",
"of",
"MLH1",
"may",
"also",
"lead",
"to",
"low-level",
"microsatellite",
"instability.37"
] | [
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] | MGMT inactivation predisposes to G:T mismatches and chromosomal instability through futile cycles of excision and repair as well as to mutation of KRAS and TP53.9 Partial methylation of MLH1 may also lead to low-level microsatellite instability.37 |
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",
"colorectal",
"cancers",
" ",
"[26-28]."
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] | In contrast, mutations accumulate throughout life in multistage models. Genetically engineered mice and familial cancer syndromes reveal that many oncogenic mutations are also compatible with normal phenotypes [11], allowing for the possibility that many "cancer" mutations may first accumulate in normal-appearing colon very early in life. Such pretumor progression [11] more readily allows for an invasive or metastatic cancer phenotype at transformation because genetic progression is uncoupled from tumor progression (Figure 2). Rather than incremental stepwise changes in phenotype after each new mutation, a tumor phenotype may only emerge after several initially occult mutations accumulate in a single normal appearing cell. In this way our multistage model can apply to both MSI+ and MSI- cancers despite their marked differences in types of mutations because early critical mutations (whatever they are) do not visibly change phenotype but instead accumulate in normal appearing colon. Early or advanced sporadic MSI- colorectal cancers colorectal cancers [26-28]. |
1360090-02-Background-p01 | [
"Although",
"the",
"positive",
"association",
"with",
"MSI+",
"and",
"inverse",
"association",
"with",
"KRAS",
"hereditary",
"non-polyposis",
"colorectal",
"cancer",
" ",
"(HNPCC)",
"patients",
"[5,8-10],",
"thus",
"providing",
"a",
"convenient",
"discriminator",
"between",
"sporadic",
"and",
"familial",
"cases.",
"The",
"majority",
"of",
"MSI+",
"sporadic",
"tumors",
"belong",
"to",
"a",
"larger",
"CRC",
"group",
"referred",
"to",
"as",
"the",
"CpG",
"island",
"methylator",
"phenotype",
"(CIMP+)",
"that",
"is",
"characterised",
"by",
"widespread",
"hypermethylation",
"of",
"CpG",
"islands",
"located",
"with",
"gene",
"promoter",
"regions",
"[11].",
"Both",
"MSI+",
"and",
"CIMP+",
"tumors",
"are",
"thought",
"to",
"arise",
"from",
"large",
"hyperplastic",
"polyps",
"and",
"serrated",
"adenomas",
"[12,13]",
"and",
"recent",
"work",
"has",
"demonstrated",
"a",
"high",
"frequency",
"of",
"BRAF",
"mutations",
"in",
"these",
"lesions",
"[7,14,15]."
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] | Although the positive association with MSI+ and inverse association with KRAS hereditary non-polyposis colorectal cancer (HNPCC) patients [5,8-10], thus providing a convenient discriminator between sporadic and familial cases. The majority of MSI+ sporadic tumors belong to a larger CRC group referred to as the CpG island methylator phenotype (CIMP+) that is characterised by widespread hypermethylation of CpG islands located with gene promoter regions [11]. Both MSI+ and CIMP+ tumors are thought to arise from large hyperplastic polyps and serrated adenomas [12,13] and recent work has demonstrated a high frequency of BRAF mutations in these lesions [7,14,15]. |
1360090-03-Results-p01 | [
"Associations",
"between",
"BRAF",
"mutation",
"and",
"clinicopathological",
"features",
"of",
"colorectal",
"cancer."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Associations between BRAF mutation and clinicopathological features of colorectal cancer. |
1557864-05-Discussion-p03 | [
"The",
"relation",
"between",
"MMR",
"deficiency",
"and",
"platinum-drug",
"resistance",
"has",
"been",
"investigated",
"in",
"only",
"a",
"few",
"in",
"vivo",
"studies.",
"Similarly",
"to",
"our",
"result,",
"no",
"MSI",
"was",
"detected",
"by",
"Mesquita",
"et",
"al.",
"[18]",
"who",
"studied",
"34",
"ovarian",
"carcinomas",
"of",
"which",
"seven",
"did",
"not",
"respond",
"to",
"cisplatin/paclitaxel",
"therapy.",
"So",
"the",
"resistance",
"seen",
"in",
"these",
"seven",
"nonresponding",
"patients",
"was",
"also",
"not",
"associated",
"with",
"MMR",
"inactivation",
"MMR",
" ",
"inactivation."
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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 was also not associated with MMR inactivation MMR inactivation. |
3034663-04-Results-p01 | [
"In",
"the",
"second",
"LS",
"family,",
"the",
"index",
"subject,",
"one",
"sister",
"and",
"one",
"brother",
"with",
"CRC",
"(II-5;",
"II-6",
"II-5",
";",
"II-6;",
"II-7",
",",
"respectively)",
"had",
"a",
"deleterious",
"variant",
"in",
"MSH6",
"(c.3013C>T;",
"p.Arg1005X)",
"but",
"did",
"not",
"have",
"the",
"p.Lys618Ala",
"variant.",
"This",
"variant",
"was",
"present",
"in",
"only",
"three",
"of",
"four",
"unaffected",
"nephews",
"(III-2;",
"III-3;",
"III-4)",
"and",
"was",
"inherited",
"from",
"the",
"parental",
"branch,",
"in",
"which",
"there",
"was",
"no",
"familial",
"history",
"of",
"cancer.",
"Individuals",
"III-3",
"and",
"III-4",
"inherited",
"also",
"the",
"deleterious",
"variant.",
"No",
"genetic",
"testing",
"was",
"available",
"from",
"the",
"father",
"or",
"paternal",
"relatives",
"(",
"Family",
"#2",
",",
"Figure",
"3)."
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] | In the second LS family, the index subject, one sister and one brother with CRC (II-5; II-6 II-5 ; II-6; II-7 , respectively) had a deleterious variant in MSH6 (c.3013C>T; p.Arg1005X) but did not have the p.Lys618Ala variant. This variant was present in only three of four unaffected nephews (III-2; III-3; III-4) and was inherited from the parental branch, in which there was no familial history of cancer. Individuals III-3 and III-4 inherited also the deleterious variant. No genetic testing was available from the father or paternal relatives ( Family #2 , Figure 3). |
1334229-01-Abstract-p01 | [
"Abstract"
] | [
0
] | Abstract |
1266026-04-Results-p01 | [
"Mutation",
"number",
"estimates",
"with",
"respect",
"to",
"clinical",
"stage",
"may",
"be",
"biased",
"with",
"the",
"Finnish",
"data",
"because",
"it",
"includes",
"only",
"specimens",
"with",
"tissue",
"available",
"for",
"molecular",
"analysis.",
"Advanced",
"cancers",
" ",
"may",
"not",
"be",
"removed.",
"Therefore,",
"a",
"similar",
"analysis",
"was",
"performed",
"on",
"a",
"population-based",
"cancer",
"registry",
"[10]",
"from",
"the",
"United",
"States",
"of",
"America",
"(SEER",
"11",
"Regs",
"Public-Use,",
"Nov",
"2001",
"Sub",
"(1992–1999)),",
"which",
"records",
"ages",
"and",
"stages",
"at",
"diagnosis",
"regardless",
"of",
"treatment",
"(Table",
"2).",
"The",
"average",
"age",
"at",
"diagnosis",
"was",
"70.5",
"years,",
"consistent",
"with",
"an",
"estimate",
"of",
"six",
"mutations",
"to",
"colorectal",
" ",
"cancer",
"for",
"the",
"108,275",
"white",
"males",
"and",
"females",
"average",
"age",
"at",
"diagnosis",
"was",
"70.5",
"years",
"9.6%",
" ",
"of",
"all",
"cancers)",
"or",
"HNPCC",
"(N",
"=",
"29",
"or",
"2.9%",
"of",
"all",
"cancers)",
"based",
"on",
"germline",
"MLH1",
"or",
"MSH2",
"mutations",
"(Table",
"1)."
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] | Mutation number estimates with respect to clinical stage may be biased with the Finnish data because it includes only specimens with tissue available for molecular analysis. Advanced cancers may not be removed. Therefore, a similar analysis was performed on a population-based cancer registry [10] from the United States of America (SEER 11 Regs Public-Use, Nov 2001 Sub (1992–1999)), which records ages and stages at diagnosis regardless of treatment (Table 2). The average age at diagnosis was 70.5 years, consistent with an estimate of six mutations to colorectal cancer for the 108,275 white males and females average age at diagnosis was 70.5 years 9.6% of all cancers) or HNPCC (N = 29 or 2.9% of all cancers) based on germline MLH1 or MSH2 mutations (Table 1). |
1334229-02-Background-p01 | [
"According",
"to",
"the",
"paradigm",
"for",
"colorectal",
"cancer",
"development,",
"mutations",
"in",
"the",
"APC",
"and",
"K-ras",
"are",
"thought",
"to",
"contribute",
"to",
"the",
"early",
"developmental",
"stages",
"of",
"colorectal",
"cancer",
"[3].",
"However,",
"a",
"recent",
"study",
"based",
"on",
"the",
"analysis",
"of",
"APC,",
"K-ras",
"and",
"TP53",
"genes",
"concluded",
"that",
"simultaneous",
"occurrence",
"of",
"all",
"three",
"genetic",
"alterations",
"is",
"rare",
"and",
"that",
"multiple",
"genetic",
"pathways",
"may",
"be",
"relevant",
"to",
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2275286-03-Methods-p03 | [
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] | Blood from peripheral veins (2 mL) was taken from patients with 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. |
1360090-04-Discussion-p01 | [
"The",
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] | The frequencies of BRAF mutation observed in MSI- (4%) and MSI+ (39%) tumors in the present study compare favourably ( 5% tumors that are sporadic or HNPCC in origin [5,8-10]. This is a very important issue for population-based screening programs that aim to identify CRC associated with the HNPCC syndrome. Compared to the analysis of MLH1 promoter methylation, mutation at the BRAF V600E hotspot is relatively simple to detect using DNA sequencing, RFLP or the SSCP method used in the present work (Figure 1). |
2386495-01-Abstract-p01 | [
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1360090-04-Discussion-p01 | [
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" ",
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] | Similar to other studies [4,5,10,16,17] we observed BRAF mutation frequencies of 4% in MSI- tumors and 39% in MSI+ tumors (Table 1). The highest frequencies were seen in tumors showing methylation of the MLH1 promoter proximal region (46%) and in tumors with infiltrating lymphocytes (48%). BRAF mutation frequencies of up to 70–80% have been reported in sporadic MSI+, CIMP+ and MLH1-methylated CRC and polyps [7,8,15,16]. For reasons that are still unclear, BRAF mutations are approximately 5–10-fold more frequent in tumors that have characteristic features of sporadic MSI+ (ie. MLH1 methylated) and CIMP+ phenotypes. These include proximal colon location, poor differentiation, mucinous histology and infiltrating lymphocytes [13,19,20]. Interestingly however, in the present study BRAF mutations never occurred in association with KRAS mutation, were present in only 3% of CIMP- tumors and showed no association with TP53 mutation (Table 2). The observation that BRAF mutations occur only very rarely in HNPCC-related MSI+ CRC demonstrates that defective DNA mismatch repair is not involved in causing this genetic alteration. |
2386495-03-Methods-p01 | [
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] | Age, age at diagnosis; DL, duodenal lesion; dom, dominant; FGP, fundic gland polyps; NA, no available data; NI, no inheritance; Number of polyps, number of polyps at diagnosis; rec, recessive |
1557864-05-Discussion-p01 | [
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] | Next we studied the association between MMR inactivation and cisplatin resistance in these cell lines. MMR inactivation seen in SKOV3 and 2774 might result in the relative resistance to cisplatin compared to the other cell lines. On the other hand, A2780 cell lines , i.e. SKOV6 , HOC7, SKOV3, 2774, OVCAR3, KB3.1, CAOV3 and A2780. Microsatellite instability (MSI), which is a marker for MMR inactivation, was detected in three out of eight cell lines i.e. SKOV3, 2774 and A2780. This results in a frequency of MMR inactivation in ovarian cancer cell lines of 38%. The MSI in SKOV3 can be explained by the loss of MLH1 mRNA expression which, however, was not caused by promoter methylation. This is in agreement with the loss of MLH1 protein expression seen in SKOV3 described in a study of the 60 NCI cancer cell lines [44]. In concordance with our findings, 2774 was also described to be MSI [45]. One of the MSI positive A2780 sublines showed a strong methylation of the MLH1 promoter without MLH1 mRNA expression, while the other subline showed a low level of methylation and relative high mRNA expression. Strathdee et al. described that one MLH1 allele was methylated in A2780 [12] which is comparable with the methylation status we saw in A2780, moreover one of our A2780 sublines showed complete methylation. On the other hand, another study did not detect MSI in A2780 [11]. Interestingly, Aquilina and colleagues suggested there is a subpopulation of A2780 cells, estimated to be around one per 106 cells [46], which are MLH1 deficient and heterozygous for the p53phe172 mutation [46,47]. Since these cells have a growth advantage, prolonged culturing of the A2780 cell line can result in selection of this subpopulation. Thus over time, separately cultured A2780 can have varying percentages of cells belonging to this subpopulation which may explain the discrepancies in MMR status seen in the A2780 cell lines analyzed by us. |
1334229-01-Abstract-p01 | [
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0,
0,
0,
0
] | In a group of 656 unselected sporadic colorectal cancer patients, aberrations in the APC, K-ras, CTNNB1 genes, and expression of hMLH1 were investigated. Additionally, tumours were divided in groups based on molecular features and compared with respect to patient's age at diagnosis, sex, family history of colorectal cancer, tumour sub-localisation, Dukes' stage and differentiation. |
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",
"was",
"also",
"not",
"associated",
"with",
"MMR",
"inactivation.",
"In",
"contrast,",
"Samimi",
"et",
"al.",
"[52]",
"found",
"an",
"inverse",
"relation",
"between",
"MLH1",
"protein",
"expression",
"and",
"the",
"response",
"to",
"platinum-based",
"chemotherapy",
"in",
"54",
"ovarian",
"carcinomas.",
"Again,",
"the",
"number",
"of",
"ovarian",
"carcinomas",
"included",
"in",
"these",
"studies",
"is",
"small",
"and",
"no",
"further",
"conclusion",
"can",
"be",
"drawn",
"from",
"these",
"results."
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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 was also not associated with MMR inactivation. In contrast, Samimi et al. [52] found an inverse relation between MLH1 protein expression and the response to platinum-based chemotherapy in 54 ovarian carcinomas. Again, the number of ovarian carcinomas included in these studies is small and no further conclusion can be drawn from these results. |
3034663-03-Methods-p01 | [
"DNA",
"from",
"blood",
"cells",
"(familial",
"cancer",
"cases",
"and",
"controls)",
"or",
"colorectal",
"mucosa",
"of",
"normal",
"appearance",
"(sporadic",
"cases)",
"was",
"used",
"for",
"the",
"c.1852_1853AA>GC",
"sporadic",
" ",
"and",
"familial",
"CRC",
"cases"
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
5,
17,
0,
0,
0,
0,
0
] | DNA from blood cells (familial cancer cases and controls) or colorectal mucosa of normal appearance (sporadic cases) was used for the c.1852_1853AA>GC sporadic and familial CRC cases |
1557864-01-Abstract-p01 | [
"MSI",
"was",
"detected",
"in",
"three",
"of",
"the",
"eight",
"cell",
"lines",
"i.e.",
"A2780",
"(no",
"MLH1",
"mRNA",
"expression",
"due",
"to",
"promoter",
"methylation),",
"SKOV3",
"(no",
"MLH1",
"mRNA",
"expression)",
"and",
"2774",
"(no",
"altered",
"expression",
"of",
"MMR",
"genes).",
"Overall,",
"there",
"was",
"no",
"association",
"between",
"cisplatin",
"response",
"and",
"MMR",
"status",
"in",
"these",
"eight",
"cell",
"lines."
] | [
0,
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0,
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0,
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0,
0
] | MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. |
2275286-03-Methods-p01 | [
"Data",
"were",
"prospectively",
"collected",
"from",
"158",
"consecutive",
"colorectal",
"cancer",
"patients",
" ",
"who",
"received",
"surgical",
"treatments",
"in",
"the",
"National",
"Colorectal",
"Center",
"of",
"the",
"Third",
"Affiliated",
"Hospital",
"of",
"Nanjing",
"University",
"of",
"Traditional",
"Chinese",
"Medicine",
"(NUTCM)",
"from",
"October",
"2004",
"to",
"June",
"2006.",
"All",
"patients",
"signed",
"an",
"informed",
"consent",
"before",
"the",
"study.",
"Patients",
"who",
"had",
"histologically",
"proven",
"carcinoma",
"and",
"received",
"operative",
"treatment",
"in",
"our",
"hospital",
"were",
"included",
"in",
"the",
"study.",
"Patients",
"were",
"excluded",
"if",
"they:",
"(1)",
"had",
"evidence",
"of",
"concomitant",
"ulcerative",
"colitis,",
"(2)",
"presented",
"with",
"clinically",
"unresectable",
"diseases,",
"(3)",
"were",
"diagnosed",
"with",
"FAP",
"and",
"other",
"polyposis",
"syndromes,",
"(4)",
"refused",
"operative",
"treatment",
"or",
"refused",
"to",
"participate",
"in",
"the",
"study.",
"This",
"study",
"was",
"approved",
"by",
"the",
"ethical",
"committee",
"of",
"the",
"NUTCM."
] | [
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] | Data were prospectively collected from 158 consecutive colorectal cancer patients who received surgical treatments in the National Colorectal Center of the Third Affiliated Hospital of Nanjing University of Traditional Chinese Medicine (NUTCM) from October 2004 to June 2006. All patients signed an informed consent before the study. Patients who had histologically proven carcinoma and received operative treatment in our hospital were included in the study. Patients were excluded if they: (1) had evidence of concomitant ulcerative colitis, (2) presented with clinically unresectable diseases, (3) were diagnosed with FAP and other polyposis syndromes, (4) refused operative treatment or refused to participate in the study. This study was approved by the ethical committee of the NUTCM. |
1360090-04-Discussion-p01 | [
"In",
"order",
"to",
"determine",
"whether",
"the",
"characteristic",
"clinicopathological",
"features",
"of",
"tumors",
"with",
"BRAF",
"mutation",
"were",
"due",
"to",
"their",
"close",
"association",
"with",
"MSI+",
"and",
"CIMP+,",
"we",
"stratified",
"tumours",
"according",
"to",
"these",
"phenotypes.",
"Despite",
"having",
"only",
"9",
"MSI-/BRAF",
"mutant",
"and",
"5",
"CIMP-/BRAF",
"mutant",
"tumors,",
"the",
"results",
"showed",
"that",
"associations",
"between",
"BRAF",
"mutation",
"and",
"the",
"morphological",
"properties",
"of",
"tumor-infiltrating",
"infiltrating",
"lymphocytes,",
"poor",
"histological",
"grade",
"and",
"mucinous",
"phenotype",
"were",
"retained",
"(Tables",
"3",
"and",
"4)."
] | [
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] | In order to determine whether the characteristic clinicopathological features of tumors with BRAF mutation were due to their close association with MSI+ and CIMP+, we stratified tumours according to these phenotypes. Despite having only 9 MSI-/BRAF mutant and 5 CIMP-/BRAF mutant tumors, the results showed that associations between BRAF mutation and the morphological properties of tumor-infiltrating infiltrating lymphocytes, poor histological grade and mucinous phenotype were retained (Tables 3 and 4). |
1360090-04-Discussion-p01 | [
"Discussion"
] | [
0
] | Discussion |
1266026-04-Results-p01 | [
"Mutation",
"number",
"estimates",
"with",
"respect",
"to",
"clinical",
"stage",
"may",
"be",
"biased",
"with",
"the",
"Finnish",
"data",
"because",
"it",
"includes",
"only",
"specimens",
"with",
"tissue",
"available",
"for",
"molecular",
"analysis.",
"Advanced",
"cancers",
"may",
"not",
"be",
"removed.",
"Therefore,",
"a",
"similar",
"analysis",
"was",
"performed",
"on",
"a",
"population-based",
"cancer",
"registry",
"[10]",
"from",
"the",
"United",
"States",
"of",
"America",
"(SEER",
"11",
"Regs",
"Public-Use,",
"Nov",
"2001",
"Sub",
"(1992–1999)),",
"which",
"records",
"ages",
"and",
"stages",
"at",
"diagnosis",
"regardless",
"of",
"treatment",
"(Table",
"2).",
"The",
"average",
"age",
"at",
"diagnosis",
"was",
"70.5",
"years,",
"consistent",
"with",
"an",
"estimate",
"of",
"six",
"mutations",
"to",
"colorectal",
"cancer",
"for",
"the",
"108,275",
"white",
"males",
"and",
"females",
"with",
"stage",
"data.",
"Like",
"the",
"Finnish",
"cancers",
"cancers",
")",
"or",
"HNPCC",
"(N",
"=",
"29",
"cancers",
")",
"or",
"HNPCC",
"(N",
"=",
"29",
"or",
"2.9%",
"of",
"all",
"cancers)",
"based",
"on",
"germline",
"MLH1",
"or",
"MSH2",
"mutations",
"(Table",
"1)."
] | [
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0
] | Mutation number estimates with respect to clinical stage may be biased with the Finnish data because it includes only specimens with tissue available for molecular analysis. Advanced cancers may not be removed. Therefore, a similar analysis was performed on a population-based cancer registry [10] from the United States of America (SEER 11 Regs Public-Use, Nov 2001 Sub (1992–1999)), which records ages and stages at diagnosis regardless of treatment (Table 2). The average age at diagnosis was 70.5 years, consistent with an estimate of six mutations to colorectal cancer for the 108,275 white males and females with stage data. Like the Finnish cancers cancers ) or HNPCC (N = 29 cancers ) or HNPCC (N = 29 or 2.9% of all cancers) based on germline MLH1 or MSH2 mutations (Table 1). |
1619718-04-Results-p01 | [
"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)."
] | [
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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). |
1619718-04-Results-p01 | [
"Frequency",
"of",
"KRAS",
"and",
"BRAF",
"mutation",
"and",
"loss",
"of",
"expression",
"of",
"O-6-methylguanine",
"DNA",
"methyltransferase",
"(MGMT)",
"by",
"polyp",
"type"
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Frequency of KRAS and BRAF mutation and loss of expression of O-6-methylguanine DNA methyltransferase (MGMT) by polyp type |
1334229-01-Abstract-p01 | [
"The",
"early",
"to",
"intermediate",
"stages",
"of",
"the",
"majority",
"of",
"colorectal",
"Netherlands",
" ",
"Cohort",
"Study"
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
25,
0,
0,
0
] | The early to intermediate stages of the majority of colorectal Netherlands Cohort Study |
1557864-03-Methods-p02 | [
"Quantitative",
"RT-PCR"
] | [
0,
0
] | Quantitative RT-PCR |
1619718-03-Materials-and-methods-p01 | [
"**",
"IGNORE",
"LINE",
"**"
] | [
0,
0,
0,
0
] | ** IGNORE LINE ** |
2275286-04-Results-p02 | [
"The",
"mutation",
"between",
"the",
"MSI-L",
"and",
"MSI-H"
] | [
0,
0,
0,
0,
0,
0,
0
] | The mutation between the MSI-L and MSI-H |
1373649-03-Methods-p01 | [
"As",
"screening",
"method",
"for",
"HNPCC",
"we",
"searched",
"for",
"MSI",
"in",
"the",
"proband's",
"primary",
"tumor",
"and",
"metastasis",
"tissue",
"blocks.",
"The",
"absence",
"of",
"proband's",
"three",
"proband",
"relatives",
" ",
"and",
"their",
"consent",
"for",
"release",
"of",
"medical",
"records",
"and",
"use",
"of",
"the",
"pathological",
"tissue",
"blocks",
"still",
"available."
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
9,
11,
9,
10,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | As screening method for HNPCC we searched for MSI in the proband's primary tumor and metastasis tissue blocks. The absence of proband's three proband relatives and their consent for release of medical records and use of the pathological tissue blocks still available. |
2386495-01-Abstract-p01 | [
"Results"
] | [
0
] | Results |
1334229-03-Methods-p01 | [
"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."
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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. |
1557864-01-Abstract-p01 | [
"No",
"MMR",
"inactivation",
"MSH6",
"ovarian",
"cancer"
] | [
7,
8,
8,
21,
1,
2
] | No MMR inactivation MSH6 ovarian cancer |
3034663-03-Methods-p01 | [
"Families",
"carrying",
"the",
"p.Lys618Ala",
"variant"
] | [
0,
0,
0,
0,
0
] | Families carrying the p.Lys618Ala variant |
1601966-03-Results-p03 | [
"Individual",
"chromosomal",
"islands",
"with",
"gain",
"of",
"expression"
] | [
0,
0,
0,
0,
0,
0,
0
] | Individual chromosomal islands with gain of expression |
1619718-04-Results-p01 | [
"Frequency",
"of",
"KRAS",
"and",
"BRAF",
"mutation",
"and",
"loss",
"of",
"expression",
"of",
"O-6-methylguanine",
"DNA",
"methyltransferase",
"(MGMT)",
"by",
"polyp",
"type"
] | [
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Frequency of KRAS and BRAF mutation and loss of expression of O-6-methylguanine DNA methyltransferase (MGMT) by polyp type |
1601966-02-Background-p01 | [
"In",
"tumors",
"tumor",
" ",
"stages",
"or",
"on",
"the",
"identification",
"of",
"new",
"tumor",
"subclasses",
"and",
"their",
"diagnostic",
"gene",
"expression",
"signatures",
"[1-6].",
"In",
"contrast,",
"much",
"less",
"is",
"known",
"about",
"the",
"influence",
"of",
"chromosomal",
"neighborhood",
"on",
"gene",
"expression",
"in",
"tumors."
] | [
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] | In tumors tumor stages or on the identification of new tumor subclasses and their diagnostic gene expression signatures [1-6]. In contrast, much less is known about the influence of chromosomal neighborhood on gene expression in tumors. |
2275286-01-Abstract-p01 | [
"Thirty-four",
"out",
"of",
"the",
"146",
"colorectal",
"cancers",
"(CRCs,",
"23.2%)",
"were",
"MSI,",
"including",
"19",
"MSI-H",
"CRCs",
"and",
"15",
"MSI-L",
"CRCS.",
"Negative",
"staining",
"for",
"MSH2",
"was",
"found",
"in",
"8",
"CRCs,",
"negative",
"staining",
"for",
"MSH6",
"was",
"found",
"in",
"6",
"CRCs.",
"One",
"MSI-H",
"CRC",
"was",
"negative",
"for",
"both",
"MSH6",
"and",
"MSH2.",
"Seventeen",
"CRCs",
"stained",
"negatively",
"for",
"MLH1.",
"MLH1",
"promoter",
"methylation",
"was",
"determined",
"in",
"34",
"MSI",
"CRCs.",
"Hypermethylation",
"of",
"the",
"MLH1",
"promoter",
"occurred",
"in",
"14",
"(73.7%)",
"out",
"of",
"19",
"MSI-H",
"CRCs",
"and",
"5",
"(33.3%)",
"out",
"of",
"15",
"MSI-L",
"CRCs.",
"Among",
"the",
"34",
"MSI",
"carriers",
"and",
"one",
"MSS",
"CRC",
"with",
"MLH1",
"negative",
"staining,",
"8",
"had",
"a",
"MMR",
"gene",
"germline",
"mutation,",
"which",
"accounted",
"for",
"23.5%",
"of",
"all",
"MSI",
"colorectal",
"cancers",
"and",
"5.5%",
"of",
"all",
"the",
"colorectal",
"cancers",
"MSH6",
" ",
"and",
"MLH1",
"on",
"tissue",
"microarrays",
"(TMAs)",
"was",
"performed,",
"and",
"methylation",
"of",
"the",
"MLH1",
"promoter",
"was",
"analyzed",
"by",
"quantitative",
"methylation",
"specific",
"PCR",
"(MSP).",
"Germline",
"mutation",
"analysis",
"of",
"blood",
"samples",
"was",
"performed",
"for",
"MSH2",
",",
"MSH6",
" ",
"and",
"MLH1",
"genes."
] | [
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] | Thirty-four out of the 146 colorectal cancers (CRCs, 23.2%) were MSI, including 19 MSI-H CRCs and 15 MSI-L CRCS. Negative staining for MSH2 was found in 8 CRCs, negative staining for MSH6 was found in 6 CRCs. One MSI-H CRC was negative for both MSH6 and MSH2. Seventeen CRCs stained negatively for MLH1. MLH1 promoter methylation was determined in 34 MSI CRCs. Hypermethylation of the MLH1 promoter occurred in 14 (73.7%) out of 19 MSI-H CRCs and 5 (33.3%) out of 15 MSI-L CRCs. Among the 34 MSI carriers and one MSS CRC with MLH1 negative staining, 8 had a MMR gene germline mutation, which accounted for 23.5% of all MSI colorectal cancers and 5.5% of all the colorectal cancers MSH6 and MLH1 on tissue microarrays (TMAs) was performed, and methylation of the MLH1 promoter was analyzed by quantitative methylation specific PCR (MSP). Germline mutation analysis of blood samples was performed for MSH2 , MSH6 and MLH1 genes. |
1334229-03-Methods-p03 | [
"Statistical",
"analysis"
] | [
0,
0
] | Statistical analysis |
1360090-04-Discussion-p01 | [
"In",
"order",
"to",
"determine",
"whether",
"the",
"characteristic",
"clinicopathological",
"features",
"of",
"tumors",
"with",
"BRAF",
"mutation",
"were",
"due",
"to",
"their",
"close",
"association",
"with",
"MSI+",
"and",
"CIMP+,",
"we",
"stratified",
"tumours",
"according",
"to",
"these",
"phenotypes.",
"Despite",
"having",
"only",
"9",
"MSI-/BRAF",
"mutant",
"and",
"5",
"CIMP-/BRAF",
"mutant",
"tumors,",
"the",
"results",
"showed",
"that",
"associations",
"between",
"BRAF",
"mutation",
"and",
"the",
"morphological",
"properties",
"of",
"tumor-infiltrating",
"infiltrating",
"lymphocytes,",
"poor",
"histological",
"grade",
"and",
"mucinous",
"phenotype",
"were",
"retained",
"(Tables",
"3",
"and",
"4)."
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] | In order to determine whether the characteristic clinicopathological features of tumors with BRAF mutation were due to their close association with MSI+ and CIMP+, we stratified tumours according to these phenotypes. Despite having only 9 MSI-/BRAF mutant and 5 CIMP-/BRAF mutant tumors, the results showed that associations between BRAF mutation and the morphological properties of tumor-infiltrating infiltrating lymphocytes, poor histological grade and mucinous phenotype were retained (Tables 3 and 4). |
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",
"TA.",
"MGMT",
"immunstaining",
"not",
"performed",
"in",
"15",
"polyps",
"(seven",
"HPs,",
"one",
"SSA,",
"one",
"MP",
"and",
"six",
"TAs)."
] | [
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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). |
2386495-03-Methods-p01 | [
"Age,",
"age",
"at",
"diagnosis;",
"DL,",
"duodenal",
"lesion;",
"dom,",
"dominant;",
"FGP,",
"fundic",
"gland",
"polyps;",
"NA,",
"no",
"available",
"data;",
"NI,",
"no",
"inheritance;",
"Number",
"of",
"polyps,",
"number",
"of",
"polyps",
"at",
"diagnosis;",
"rec,",
"recessive"
] | [
0,
0,
0,
0,
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0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | Age, age at diagnosis; DL, duodenal lesion; dom, dominant; FGP, fundic gland polyps; NA, no available data; NI, no inheritance; Number of polyps, number of polyps at diagnosis; rec, recessive |
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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0,
0
] | 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). |
3034663-04-Results-p01 | [
"In",
"the",
"second",
"LS",
"family,",
"the",
"index",
"subject,",
"one",
"sister",
"and",
"one",
"brother",
"with",
"CRC",
"(II-5;",
"II-6;",
"II-7,",
"respectively)",
"had",
"a",
"deleterious",
"variant",
"in",
"MSH6",
"(c.3013C>T;",
"p.Arg1005X)",
"but",
"did",
"not",
"have",
"the",
"p.Lys618Ala",
"variant.",
"This",
"variant",
"was",
"present",
"in",
"only",
"three",
"of",
"four",
"unaffected",
"nephews",
"(III-2;",
"III-3;",
"III-4)",
"and",
"was",
"inherited",
"from",
"the",
"parental",
"branch,",
"in",
"which",
"there",
"was",
"no",
"familial",
"history",
"of",
"cancer.",
"Individuals",
"III-3",
"and",
"III-4",
"inherited",
"also",
"the",
"deleterious",
"variant.",
"No",
"genetic",
"testing",
"was",
"available",
"from",
"the",
"father",
"or",
"paternal",
"relatives",
"(Family",
"#2,",
"Figure",
"3)."
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] | In the second LS family, the index subject, one sister and one brother with CRC (II-5; II-6; II-7, respectively) had a deleterious variant in MSH6 (c.3013C>T; p.Arg1005X) but did not have the p.Lys618Ala variant. This variant was present in only three of four unaffected nephews (III-2; III-3; III-4) and was inherited from the parental branch, in which there was no familial history of cancer. Individuals III-3 and III-4 inherited also the deleterious variant. No genetic testing was available from the father or paternal relatives (Family #2, Figure 3). |