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

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.

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."

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). A weighted PRS comprised of adenoma-risk SNPs was associated with higher cumulative adenomas (weighted rate ratio = 1.57; P = 0.03).

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.

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.