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 ( < 0.05): rs12241008 (gene: ), rs2423279 (), rs3184504 (), and rs961253 (), 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 ( < 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; = 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.