Abstract 4464: Genetic variants at chromosome 8q24, colorectal epithelial cell proliferation, and risk for incident, sporadic colorectal adenomas

Abstract

Three polymorphic sites at chromosome 8q24 (rs7837328, rs10808555, and rs6983267) have been associated with risk for colorectal adenomas. It was also previously reported that the rs6983267 single nucleotide polymorphism (SNP) may enhance Wnt signaling, which regulates cell proliferation. To investigate associations between the 8q24 variants and colorectal epithelial cell proliferation in the normal-appearing colorectal mucosa, as well as risk for colorectal adenoma, we analyzed data from a previously conducted pilot, colonoscopy-based case-control study of incident, sporadic colorectal adenoma among the White participants (n = 90 cases, 132 controls). Proliferation was measured in biopsies of the normal-appearing mucosa of the rectum, sigmoid colon, and cecum using immunohistochemistry for proliferating cell nuclear antigen (PCNA) and calculated as a labeling index averaged across all three colorectal sites. Each SNP was associated with risk for colorectal adenoma in the same direction as previously reported; the odds ratios (ORs) for those homozygous for the rs7837328, rs10808555, and rs6983267 risk alleles relative to those heterozygous or homozygous for the non-risk alleles combined were, respectively, 2.07 (95% confidence interval [CI] 1.07-3.97), 2.37 (CI 0.97-5.76), and 1.55 (CI 0.86-2.79). Colorectal epithelial cell proliferation tended to be higher among those homozygous for the risk alleles (alleles A, G, and G for SNPs rs7837328, rs10808555, and rs6983267, respectively) compared to those heterozygous or homozygous for the non-risk alleles combined; in the cases and controls combined, for those with the rs7837328 AA genotype proliferation was 6.7% higher (p = 0.40), for those with the rs10808555 GG genotype it was 16.5% higher (p = 0.12), and for those with the rs6983267 GG genotype it was 1.2% higher (p = 0.87). These preliminary findings, which are consistent with previously reported direct associations between genetic variants at chromosome 8q24 and risk for colorectal adenoma, suggest that the genetic variants may also be associated with higher levels of colorectal epithelial cell proliferation in humans, thus providing support for the hypothesis that 8q24 variants may increase risk via enhanced Wnt signaling.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4464. doi:1538-7445.AM2012-4464