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, lowpenetrant 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.

dx.doi.org/10.1136/jmedgenet-2013-102000, hdl.handle.net/1765/68365
Journal of Medical Genetics
Department of Neurology

Hes, F.J, Ruano, D, Nieuwenhuis, M.H, Tops, C, Schrumpf, M, Nielsen, M, … van Wezel, T. (2014). Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis. Journal of Medical Genetics, 51(1), 55–60. doi:10.1136/jmedgenet-2013-102000