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Genetic Colorectal Cancer Risk Variants are Associated with Increasing Adenoma Counts

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Background: High lifetime counts of pre-cancerous polyps, termed “adenomas,” are associated with increased risk for colorectal cancer (CRC). Given that a genetic predisposition to adenomas may increase susceptibility to CRC, further studies are needed to characterize low-penetrance germline factors in those with increased cumulative adenoma counts.

Purpose: To investigate if known CRC or adenomarisk single nucleotide polymorphisms (SNPs) are associated with increasing cumulative adenoma counts in a prospective screening cohort of veterans.

Data Analysis: The CSP #380 screening colonoscopy cohort includes a biorepository of selected individuals with baseline advanced neoplasia and matched individuals without neoplasia (n=612). Blood samples were genotyped using the Illumina Infinium Omni2.5-8 GWAS chip and associated cumulative adenoma counts were summed over 10 years. A corrected Poisson regression (adjusted for age at last colonoscopy, gender, and race) was used to evaluate associations between higher cumulative adenoma counts and 43 pre-specified CRC-risk SNPs or a subset of these SNPs shown also to be associated with adenomas in published literature. SNPs were evaluated singly or combined in a Genetic Risk Score (GRS). The GRS was constructed from only the eight adenomarisk SNPs and calculated based on the total number of present risk alleles (0-2) summed across all SNPs per individual (both weighted for published effect size and unweighted).

Results: Four CRC-risk SNPs were associated with increasing mean 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. Only one known adenoma-risk SNP was significant in our dataset (rs961253; OR 1.23 per risk allele; P=0.01). An increasing weighted GRS was associated with increased cumulative adenoma counts (weighted RR 1.58, P=0.03; unweighted RR 1.03, P=0.39).

Implications: In this CRC screening cohort, four known CRC-risk SNPs were found to be associated with increasing cumulative adenoma counts. Additionally, an increasing burden of adenoma-risk SNPs, as measured by a weighted GRS, was associated with higher cumulative adenoma counts. Future work will evaluate predictive tools based on a precancerous, adenoma GRS to better risk stratify patients during CRC screening, and compare to current CRC genetic risk scores.

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