PLoS ONE (Jan 2014)

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

  • Anna Abulí,
  • Luis Bujanda,
  • Jenifer Muñoz,
  • Stephan Buch,
  • Clemens Schafmayer,
  • Maria Valeria Maiorana,
  • Silvia Veneroni,
  • Tom van Wezel,
  • Tao Liu,
  • Helga Westers,
  • Clara Esteban-Jurado,
  • Teresa Ocaña,
  • Josep M Piqué,
  • Montserrat Andreu,
  • Rodrigo Jover,
  • Angel Carracedo,
  • Rosa M Xicola,
  • Xavier Llor,
  • Antoni Castells,
  • EPICOLON Consortium,
  • Malcolm Dunlop,
  • Robert Hofstra,
  • Annika Lindblom,
  • Juul Wijnen,
  • Paolo Peterlongo,
  • Jochen Hampe,
  • Clara Ruiz-Ponte,
  • Sergi Castellví-Bel

DOI
https://doi.org/10.1371/journal.pone.0095022
Journal volume & issue
Vol. 9, no. 4
p. e95022

Abstract

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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.