Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis

FJ Hes, D Ruano, M Nieuwenhuis, CM Tops, M Schrumpf, M Nielsen, PEA Huijts, JT Wijnen, Anja Wagner, EBG Garcia, RH Sijmons, FH Menko, TGW Letteboer, N Hoogerbrugge, J Harryvan, E Kampman, H Morreau, HFA Vasen, T van Wezel

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Abstract

Background Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. Methods We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). Results We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. Conclusions These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.
Original languageUndefined/Unknown
Pages (from-to)55-60
Number of pages6
JournalJournal of Medical Genetics
Volume51
Issue number1
DOIs
Publication statusPublished - 2014

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