Influence of Genetic Polymorphisms in Prostaglandin E2 Pathway (COX-2/HPGD/SLCO2A1/ABCC4) on the Risk for Colorectal Adenoma Development and Recurrence after Polypectomy

Abstract

OBJECTIVES: Deregulation of prostaglandin E2 (PGE2) levels reported in colorectal carcinogenesis contributes to key steps of cancer development. Our aim was to evaluate the influence of the genetic variability in COX-2/HPGD/SLCO2A1/ABCC4 PGE2 pathway genes on the development and recurrence of colorectal adenomas. METHODS: A case-control study was conducted gathering 480 unscreened individuals and 195 patients with personal history of adenomas. A total of 43 tagSNPs were characterized using the Sequenom platform or real-time PCR. RESULTS: Ten tagSNPs were identified as susceptibility biomarkers for the development of adenomas. The top three most meaningful tagSNPs include the rs689466 in COX-2 (odds ratio (OR)=3.23; 95% confidence interval (CI): 1.52-6.86), rs6439448 in SLCO2A1 (OR=0.38; 95% CI: 0.22-0.65) and rs1751051 in ABCC4 genes (OR=2.75; 95% CI: 1.58-4.80). The best four-locus gene-gene interaction model included the rs1346271, rs1863642 and rs12500316 single nucleotide polymorphisms in HPGD and rs1678405 in ABCC4 genes and was associated with a 13-fold increased susceptibility (95% CI: 3.84-46.3, P<0.0001, cross-validation (CV) accuracy: 0.78 and CV consistency: 8/10). Interesting, in low-risk patients the ABCC4 rs9524821AA genotype was associated not only with a higher hazard ratio (HR=2.93; 95% CI: 1.07-8.03), but half of these patients had adenoma recurrence at 60 months, considerably higher than the 21% noticed in low-risk patients. CONCLUSIONS: Genetic polymorphisms in COX-2/PGE2 pathway appear to contribute to the development of colorectal adenomas and influence the interval time to adenomas recurrence. The definition of risk models through the inclusion of genetic biomarkers might improve the adherence and optimization of current screening and surveillance guidelines for colorectal cancer prevention.Financial support: This study was supported by a research grant from the Instituto Português de Oncologia do Porto— Centro de Investigação. Furthermore, C.P. was a recipient of a PhD grant (SFRH/BD/64805/2009) from FCT— Fundacão para a Ciência e Tecnologia, co-financed by European Social Funds (ESF) under Human Potential Operation Programme (POPH) from National Strategic Reference Framework (NSRF) and Liga Portuguesa Contra o Cancro—Núcleo Regional do Norte. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio