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

Abulí, Anna; Andreu Camps, Montserrat; Castellví Bel, Sergi

doi:http://dx.doi.org/10.1371/journal.pone.0095022

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

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Abulí A, Bujanda L, Muñoz J, Buch S, Schafmayer C, Maiorana MV, et al. The MLH1 c.1852_1853delinsGC (p.K618A) variant in colorectal cancer: genetic association study in 18,723 individuals. PLoS ONE. 2014 Apr 17;9(4):e95022. DOI: 10.1371/journal.pone.0095022

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.