Genetic Colorectal Cancer and Adenoma Risk Variants are Associated with Increasing Adenoma Counts.

The genetic basis for most individuals with high cumulative lifetime colonic adenomas is unknown. We investigated associations between known colorectal cancer (CRC)-risk single nucleotide polymorphisms (SNPs) and increasing cumulative adenoma counts. The Cooperative Studies Program #380 screening colonoscopy cohort includes 612 selected participants age 50-75 with genotyped blood samples and 10 years of clinical follow up. We evaluated 41 published 'CRC-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.' Four CRC-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 (RR) of 1.31, 1.29, 1.24, and 1.23, respectively. Three CRC-risk SNPs were associated with 10+ cumulative adenomas (p<0.05), with risk allele odds ratios (OR) of 2.09 (rs3184504), 2.30 (rs961253), and 1.94 (rs3217901). A weighted adenoma-risk SNP PRS was associated with higher cumulative adenomas (weighted RR 1.57, p=0.03). In this mostly male Veteran CRC screening cohort, several known CRC-risk SNPs were associated with increasing cumulative adenoma counts and the finding of 10+ cumulative adenomas. Additionally, an increasing burden of adenoma-risk SNPs, measured by a weighted PRS, was associated with higher cumulative adenomas. Future work will seek to validate these findings in different populations, and then augment current CRC risk prediction tools with precancerous, adenoma genetic data. Copyright ©2020, American Association for Cancer Research.