Dataset Information

The MLH1 c.1852_1853delinsGC (p.K618A) variant in colorectal cancer: genetic association study in 18,723 individuals.

ABSTRACT: Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance", being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.

SUBMITTER: Abuli A

PROVIDER: S-EPMC3990597 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The MLH1 c.1852_1853delinsGC (p.K618A) variant in colorectal cancer: genetic association study in 18,723 individuals.

Abulí Anna A Bujanda Luis L Muñoz Jenifer J Buch Stephan S Schafmayer Clemens C Valeria Maiorana Maria M Veneroni Silvia S van Wezel Tom T Liu Tao T Westers Helga H Esteban-Jurado Clara C Ocaña Teresa T Piqué Josep M JM Andreu Montserrat M Jover Rodrigo R Carracedo Angel A Xicola Rosa M RM Llor Xavier X Castells Antoni A Dunlop Malcolm M Hofstra Robert R Lindblom Annika A Wijnen Juul J Peterlongo Paolo P Hampe Jochen J Ruiz-Ponte Clara C Castellví-Bel Sergi S

PloS one 20140417 4

Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond ...[more]

PMID: 24743384

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Project description:Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected - that is, with HNPCC-related cancer diagnosis - and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (P<0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families.

Project description:Purpose:Several studies have proved that single nucleotide polymorphisms (SNPs) of mismatch repair system genes are closely related to the development of colorectal cancer (CRC) by causing microsatellite instability, while effects of the SNPs of MMR system-related genes on the clinical outcomes of cytotoxic chemotherapy are less understood. The aim of this study explored the influence of MLH1 SNPs on clinical outcomes of first-line irinotecan-based chemotherapy in CRC. Patients and methods:A total of 125 metastatic colorectal cancer (mCRC) patients who received first-line irinotecan-based chemotherapy (none of them combined with bevacizumab or cetuximab) were enrolled in this study. Blood samples or formalin-fixed paraffin-embedded tissues of study population were taken. DNA isolation and genotyping analyzed were obtained for potential functional polymorphisms of MLH1 rs1800734 by real-time PCR. Progression-free survival (PFS) was the primary endpoint and tumor response rate (RR) was the secondary endpoint of this study. Results:Of all the assessable population, the result showed no statistical difference among the three types SNPs of MLH1 rs1800734 (AA, AG, GG) for RR (P=0.859), and also without significant difference for AA + AG combined variants vs GG variant (P=0.849). The median PFS for AA, AG, and GG variants of MLH1 rs1800734 SNPs were 9.4 months, 7.0 months, and 6.9 months, respectively (log-rank P=0.031). Interestingly, compared with AA variant of MLH1 rs1800734 SNPs, GG variant showed a shorter PFS (HR: 3.49; 95 CI: 1.02-11.94; P=0.046). Furthermore, the median PFS of AA + AG combined variants and GG variant were 8.3 months and 6.9 months (log-rank P=0.037), and GG variant have a decreased trend with no significant difference (HR: 1.57; 95 CI: 0.98-2.53; P=0.061). Conclusion:The AA variant of MLH1 rs1800734 SNPs has a longer PFS in first-line irinotecan-based chemotherapy for mCRC patients, and the result needs to be further confirmed by prospective studies in the future.

Project description:BACKGROUND:The development of colorectal cancer (CRC) is a complicated multistep process that involves an accumulation of mutations in tumor suppressor genes and oncogenes. In the process of DNA replication, base mismatch often occurs due to various factors leading to abnormal expression of mismatch repair genes (MMR), among which MLH1 and MSH2 are the most important. Recently, numerous studies indicated that MLH1/MSH2 phenotype is associated with CRC. We wanted to elucidate the role of MLH1/MSH2 in the prediction and prognosis of CRC through long-term clinical observation. AIM:To evaluate the prognostic and predictive significance of MLH1/MSH2 in patients with stage II-III CRC using immunohistochemical analysis and GeneScan. METHODS:Specimens from 681 patients with CRC (395 stage II and 286 stage III, 387 males and 294 females) who underwent curative surgical resection from 2013 to 2016 were tested. Immunohistochemistry was used to analyze MMR status and the microsatellite status of 133 patients was determined by GeneScan analysis. RESULTS:Five hundred and fifty (80.76%) patients were MLH1/MSH2 positive and 131 (19.24%) were negative by immunohistochemistry. MLH1/MSH2-positive tumors were significantly more frequent in the colon than in the rectum, and had poor differentiation and less mucin production (P < 0.05). Patients of different groups did not differ in terms of age, gender, tumor size, tumor stage, lymphocytic infiltration, or circumscribed margin. MLH1/MSH2-negative patients had a more favorable OS than MLH1/MSH2-positive patients (P < 0.001). Univariate and multivariate analyses demonstrated MLH1/MSH2 expression as an independent prognostic and predictive factor for stage II/III CRC. MLH1/MSH2 expression was a strong prognostic factor in all patients [P < 0.001, hazard ratio (HR) = 4.064, 95%CI: 2.241-7.369]. Adjuvant chemotherapy had a greater correlation with survival advantage in MLH1/MSH2-negative patients with stage III disease (P < 0.001, HR = 7.660, 95%CI: 2.974-15.883). However, patients with stage II disease or MLH1/MSH2-positive patients with stage III disease did not benefit from adjuvant chemotherapy. GeneScan analysis demonstrated that among 133 patients, 105 (78.95%) were microsatellite stable, and 28 (21.05%) had microsatellite instability (MSI), including 18 (13.53%) with high MSI and 10 (7.52%) with low MSI. This is consistent with the immunohistochemical results. CONCLUSION:MLH1/MSH2 phenotype constitutes a pathologically and clinically distinct subtype of sporadic CRC. MLH1/MSH2 is an independent prognostic and predictive factor for outcome of stage II-III CRC.

Dataset Information

The MLH1 c.1852_1853delinsGC (p.K618A) variant in colorectal cancer: genetic association study in 18,723 individuals.

Publications

The MLH1 c.1852_1853delinsGC (p.K618A) variant in colorectal cancer: genetic association study in 18,723 individuals.

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