Genetic variation in prostaglandin synthesis and related pathways, NSAID use and colorectal cancer risk in the Colon Cancer Family Registry - PubMed (original) (raw)

doi: 10.1093/carcin/bgu119. Epub 2014 Jun 7.

Karen W Makar 2, Laura Heath 1, John Whitton 2, John D Potter 3, Elizabeth M Poole 4, Nina Habermann 5, Dominique Scherer 5, David Duggan 6, Hansong Wang 7, Noralane M Lindor 8, Michael N Passarelli 1, John A Baron 9, Polly A Newcomb 10, Loic Le Marchand 7, Cornelia M Ulrich 11

Affiliations

Alexa J Resler et al. Carcinogenesis. 2014 Sep.

Abstract

Although use of non-steroidal anti-inflammatory drugs (NSAIDs) generally decreases colorectal cancer (CRC) risk, inherited genetic variation in inflammatory pathways may alter their potential as preventive agents. We investigated whether variation in prostaglandin synthesis and related pathways influences CRC risk in the Colon Cancer Family Registry by examining associations between 192 single nucleotide polymorphisms (SNPs) and two variable nucleotide tandem repeats (VNTRs) within 17 candidate genes and CRC risk. We further assessed interactions between these polymorphisms and NSAID use on CRC risk. Using a case-unaffected-sibling-control design, this study included 1621 primary invasive CRC cases and 2592 sibling controls among Caucasian men and women aged 18-90. After adjustment for multiple comparisons, two intronic SNPs were associated with rectal cancer risk: rs11571364 in ALOX12 [OR(het/hzv) = 1.87, 95% confidence interval (CI) = 1.19-2.95, P = 0.03] and rs45525634 in PTGER2 (OR(het/hzv) = 0.49, 95% CI = 0.29-0.82, P = 0.03). Additionally, there was an interaction between NSAID use and the intronic SNP rs2920421 in ALOX12 on risk of CRC (P = 0.03); among those with heterozygous genotypes, risk was reduced for current NSAID users compared with never or former users (OR(het) = 0.60, 95% CI = 0.45-0.80), though not among those with homozygous wild-type or variant genotypes. The results of this study suggest that genetic variation in ALOX12 and PTGER2 may affect the risk of rectal cancer. In addition, this study suggests plausible interactions between NSAID use and variants in ALOX12 on CRC risk. These results may aid in the development of genetically targeted cancer prevention strategies with NSAIDs.

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Figures

Fig. 1.

Fig. 1.

Prostaglandin synthesis pathway. The COX enzymes COX1 and COX2, which reduce arachidonic acid to prostaglandin H2 (PGH2), are the main targets of COX2-specific inhibitors and NSAIDs. PGH2 becomes a substrate for thromboxane, prostacyclin and prostaglandin synthases, which are converted into thromboxane A2 (TXA2), PGI2, PGE2 and prostaglandin D2 (PGD2). Arachidonic lipoxygenesases and hydroperoxides (HPETEs) convert arachidonic acid into leukotrienes and other inflammation-mediating eicosanoids.

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