Journal Article

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

Sijmons, Rolf H, Harryvan, Jan, van Wezel, Tom, Ruano, Dina, García, Encarna B Gómez, Menko, Fred H, Vasen, Hans F A, Kampman, Ellen, Morreau, Hans, Wijnen, Juul T, Letteboer, Tom G W, Nielsen, Maartje, Tops, Carli M, Hes, Frederik J, Nieuwenhuis, Marry, Wagner, Anja, Schrumpf, Melanie, Huijts, Petra E A, Hoogerbrugge, Nicoline

2014

Overview

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.

• Publisher: BMJ Publishing Group LTD
• Subject: Adenomatous Polyposis Coli - complications / Adenomatous Polyposis Coli - genetics / Adolescent / Adult / Age / Age Distribution / Aged / Aged, 80 and over / Alleles / apc / Case-Control Studies / Chromosome Aberrations / Chromosomes, Human, Pair 11 / Chromosomes, Human, Pair 15 / Colorectal cancer / Colorectal Neoplasms - complications / Colorectal Neoplasms - genetics / Endoscopy / families / Families & family life / Gene Frequency / Genetic Predisposition to Disease / genetic-variants / genome-wide association / Genotype / hereditary / Humans / mechanisms / metaanalysis / Middle Aged / Mutation / mutations / Odds Ratio / Phenotype / Polymorphism, Single Nucleotide / Risk / Studies / Surveillance / susceptibility loci / Tumors / Young Adult