Effect of COX2 -765G>C and c.3618A>G polymorphisms on the risk and survival of sporadic colorectal cancer.

摘要

BACKGROUND: The COX2 gene (also known as PTGS2) encodes one of the essential cyclooxygenases for the prostanoid synthesis, and its expression is tightly regulated at both transcriptional and posttranscriptional levels. COX2 overexpression has been detected in up to 90% of colon carcinomas, and its downregulation inhibits polyp formation. Several polymorphisms located in both 5'- and 3'- flanking regions of COX2 have been described, but their functional significance and their use as prognostic indicators are still unclear. METHOD: We analyzed in Spanish population the risk contribution and the prognostic significance for colorectal cancer (CRC) with five polymorphisms (rs20417, rs20426, rs5276, rs13306035 and rs4648298) located in the coding and regulatory regions of COX2. RESULTS: Only two variants appear in Spanish population: -765G>C (rs20417) located at the promoter and c.3618A>G (rs4648298) in the 3'UTR. None of the two polymorphisms associate with colon cancer risk (HR of 1.42; 95% CI = 0.46-4.47 and 0.62; 95% CI: 0.305-1.267, respectively). Moreover, the multifactor dimensionality reduction method does not detect high- or low-risk genotype combinations (training accuracy: 0.52; testing accuracy: 0.45; cross-validation consistency (CVC): 10/10; p = 0.37), indicating that there are no synergist interactions between these polymorphisms that alter the risk of cancer. However, the variant of the c.3618A>G polymorphism is associated with the presence of several clinicopathological features that have been shown to be good prognostic indicators. In addition, patients with the c.3618A>G polymorphism also show improved survival rates (log rank, p = 0.026). CONCLUSION: The current results suggested that c.3618A>G polymorphism in COX2 is a good prognostic indicator for patients with CRC. Genotyping this polymorphism may be useful for predicting the clinical outcome of sporadic CRC.