Genetic Colorectal Cancer and Adenoma Risk Variants Are Associated with Increasing Cumulative Adenoma Counts

Background: The genetic basis for most individuals with high cumulative lifetime colonic adenomas is unknown. We investigated associations between known colorectal cancer-risk single-nucleotide polymorphisms (SNP) and increasing cumulative adenoma counts. Methods: The Cooperative Studies Program #380 screening colonoscopy cohort includes 612 selected participants age 50 to 75 with genotyped blood samples and 10 years of clinical follow-up. We evaluated 41 published "colorectal cancer-risk SNPs" for associations with individual cumulative adenoma counts or having >= 10 cumulative adenomas. SNPs were analyzed singly or combined in a polygenic risk score (PRS). The PRS was constructed from eight published SNPs associated with multiple adenomas, termed "adenoma-risk SNPs." Results: Four colorectal cancer-risk SNPs were associated with increasing cumulative adenoma counts (P < 0.05): rs12241008 (gene: VTI1A), rs2423279 (BMP2/HAO1), rs3184504 ( SH2B3), and rs961253 (FERMT1/BMP2), with risk allele risk ratios of 1.31, 1.29, 1.24, and 1.23, respectively. Three colorectal cancer-risk SNPs were associated with =10 cumulative adenomas (P < 0.05), with risk allele odds ratios of 2.09 (rs3184504), 2.30 (rs961253), and 1.94 (rs3217901). Aweighted PRS comprised of adenoma-risk SNPs was associated with higher cumulative adenomas (weighted rate ratio = 1.57; P = 0.03). Conclusions: In this mostly male veteran colorectal cancer screening cohort, several known colorectal cancer-risk SNPs were associated with increasing cumulative adenoma counts and the finding of >= 10 cumulative adenomas. In addition, an increasing burden of adenoma-risk SNPs, measured by a weighted PRS, was associated with higher cumulative adenomas. Impact: Future work will seek to validate these findings in different populations and then augment current colorectal cancer risk prediction tools with precancerous, adenoma genetic data.