TY - JOUR
T1 - The MLH1 c.1852_1853delinsGC (p.K618A) Variant in Colorectal Cancer
T2 - Genetic Association Study in 18,723 Individuals
AU - Abulí, Anna
AU - Bujanda, Luis
AU - Muñoz, Jenifer
AU - Buch, Stephan
AU - Schafmayer, Clemens
AU - Valeria Maiorana, Maria
AU - Veneroni, Silvia
AU - van Wezel, Tom
AU - Liu, Tao
AU - Westers, Helga
AU - Esteban-Jurado, Clara
AU - Ocaña, Teresa
AU - Piqué, Josep M
AU - Andreu, Montserrat
AU - Jover, Rodrigo
AU - Carracedo, Angel
AU - Xicola, Rosa M
AU - Llor, Xavier
AU - Castells, Antoni
AU - EPICOLON Consortium
AU - Dunlop, Malcolm
AU - Hofstra, Robert
AU - Lindblom, Annika
AU - Wijnen, Juul
AU - Peterlongo, Paolo
AU - Hampe, Jochen
AU - Ruiz-Ponte, Clara
AU - Castellví-Bel, Sergi
PY - 2014/4/17
Y1 - 2014/4/17
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pone.0095022
DO - 10.1371/journal.pone.0095022
M3 - Article
C2 - 24743384
SN - 1932-6203
VL - 9
SP - e95022
JO - PLoS ONE
JF - PLoS ONE
IS - 4
ER -