Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis
Hes, F.J. ; Ruano, D. ; Nieuwenhuis, M. ; Tops, C.M.J. ; Schrumpf, M. ; Nielsen, M. ; Huijts, P.E. ; Wijnen, J. ; Wagner, A. ; Gomet Garcia, E.B. ; Sijmons, R.H. ; Menko, F.H. ; Letteboer, T.G. ; Hoogerbrugge, N. ; Harryvan, J.L. ; Kampman, E. ; Morreau, H. ; Vasen, H.F. ; Wezel, T.G. van - \ 2014
Journal of Medical Genetics 51 (2014)1. - ISSN 0022-2593 - p. 55 - 60.
genome-wide association - susceptibility loci - genetic-variants - apc - mutations - hereditary - families - metaanalysis - mechanisms - phenotype
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.