Abstract 1671: Inflammatory pathway genes may have stronger associations with hyperplastic polyps than with adenomas
Authors: Coghill Anna E. , Burnett-Hartman Andrea N. , Passarelli Michael N. , Makar Karen W. , Newcomb Polly A. 
Published: August 2012

The prostaglandin synthesis pathway is critical for regulation of inflammatory processes in the colon and plays a well-defined role in colorectal carcinogenesis. Genetic variation in prostaglandin synthases, PTGS-1 (COX-1) and PTGS-2 (COX-2), and enzymes that regulate the pathway such as IαBKB and NFκB, has been linked to colorectal cancer (CRC) incidence and mortality. However, the role of variability in these genes in relation to the development of distinct subtypes of early colorectal neoplasia has not been investigated. We therefore examined polymorphisms in prostaglandin synthesis pathway genes in relation to the risk of various subtypes of colorectal polyps. Study participants were enrollees of Group Health, an integrated healthcare provider in Washington State, aged 20 to 79, who underwent colonoscopy for any indication between 1998 and 2007. We excluded those with prior CRC, ulcerative colitis, Crohn's disease, Lynch syndrome, familial adenomatous polyposis, or colectomy. Participants completed a structured interview, provided a DNA sample, and lesions discovered at colonoscopy received a standardized pathology review. HapMap was used to select 18 single nucleotide polymorphisms (SNPs) in 4 genes for investigation: 5 in PTGS-1, 4 in PTGS-2, 3 in IαBKB and 6 in NFκB. Multiplex genotyping was performed utilizing the Illumina GoldenGate assay. Polytomous logistic regression compared genetic variation between individuals free of colorectal pathology and two case groups with colorectal polyps: 1) adenomas (ADs) and 2) hyperplastic polyps (HPs). Models were adjusted for age, sex, and race. Differences by type of lesion (AD vs. HP) were considered using contrasts of regression parameters. A gene-by-gene analysis approach was taken; the false discovery rate method of Benjamini and Hochberg was applied to address multiple testing. We evaluated approximately 929 cases, including 526 with ADs and 403 with HPs, as well as 826 controls free of colorectal pathologies. We observed a statistically significant association between HPs and genetic variation in PTGS-1 (rs10306194, ORAC vs. CC: 1.26; 95% CI 0.94-1.68, ORAA vs. CC: 1.74; 95% CI 0.88-3.42, P-trend=0.04). No associations were observed for ADs. Significant heterogeneity in the association between genetic variants and colorectal polyps according to the polyp type (AD vs. HP) was observed for 1 SNP in both PTGS-2 (rs689466) and IαBKB (rs5029748) and 2 SNPs in NFκB (rs3774959, rs230510), with p-values ranging from 0.03-0.05. In each case, the variant showed evidence of an association with the risk of HPs but not ADs. Correction for multiple testing confirmed the existence of heterogeneity in associations according to type of colorectal polyp. These data suggest that genetic variation in the prostaglandin synthesis pathway may be associated with the development of specific subtypes of early colorectal neoplasia.

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 1671. doi:1538-7445.AM2012-1671