Abstract 37: Genetic variation in prostaglandin synthesis and related pathways, NSAID use, and risk of colorectal cancer in the Colon Cancer Family Registry.
Authors: Resler Alexa J. , Heath Laura , Makar Karen W. , Whitton John , Habermann Nina , Wang Hansong , Newcomb Polly A. , LeMarchand Loic , Potter John D. , Ulrich Cornelia M. 
Published: August 2013

Introduction: Inflammation is known to affect the risk of colorectal cancer (CRC). Although use of non-steroidal anti-inflammatory drugs (NSAIDs) is effective in decreasing CRC risk, inherited variation in genes that affect NSAID metabolism may alter their potential as a preventive agent. As NSAIDs function by inhibiting cyclooxygenase (COX) enzymes, which control the conversion of arachidonic acid to prostaglandins and thromboxane, we investigated whether variation in prostaglandin synthesis and related pathways affects the risk of CRC in the Colon Cancer Family Registry.

Methods: We examined associations between 221 tagging and candidate single nucleotide polymorphisms (SNPs) within 18 candidate genes (ALOX12, ALOX5, ALOX5AP, CRP, EGFR, GIPC1, HPGD, PARP12, PKN1, PLA2G1B, PTGER1, PTGER2, PTGER3, PTGER4, PTGES, PTGIS, PTGS2, and TBXAS1) and the risk of CRC. We further assessed whether the association between SNPs and CRC risk varied by use of NSAIDs. Using a case-unaffected-sibling-control design, this study included 4,213 Caucasian men and women age 20-74 with no known familial adenomatous polyposis and no personal history of ulcerative colitis or Crohn's disease. Cases (N=1,621) were recruited from six registry centers and were diagnosed with primary invasive CRC from 1998-2002. Controls (N=2,592) were siblings not diagnosed with CRC at the time of ascertainment. We computed odds ratios and 95% confidence intervals using conditional logistic regression and corrected for multiple comparisons using the Conneely and Boehnke method. All models were adjusted for age and sex; NSAID interactions were further adjusted for BMI, smoking, and physical activity.

Results: After adjustment for multiple comparisons, two intronic SNPs were associated with a decreased risk of rectal cancer: rs45525634 in PTGER2 (ORhet/hzv 0.49, 95% CI 0.29-0.82) and rs6091005 in PTGIS (ORhet 0.73, 95% CI 0.52-1.03; ORhzv 0.39, 95% CI 0.22-0.68). Additionally, an intronic SNP, rs11571364, in ALOX12 was associated with an increased risk of rectal cancer (ORhet/hzv 1.87, 95% CI 1.19-2.95). The risk of CRC associated with NSAID use differed by genotype at three intronic SNPs: rs10142849 (p = 0.02) in PTGER2 as well as rs11239516 (p = 0.04) and rs2115819 (p = 0.05) in ALOX5. These SNPs in ALOX5 shared low LD among Caucasian controls (r2 = 0.28). There was also evidence for interactions between SNP genotypes and NSAID use for colon cancer for two intronic SNPs, rs11239516 (p = 0.04) in ALOX5 and rs7806848 (p = 0.02) in TBXAS1, and for rectal cancer for rs16870224 (p = 0.05) located in the 3' UTR of PTGER4, the coding SNP rs35416389 (R641Q, p = 0.02) in PKN1, and two intronic SNPs rs17222919 (p = 0.03) in ALOX5 and rs6664305 (p = 0.01) in PTGER3.

Conclusion: The results of this study suggest that genetic variation in ALOX12, PTGER2, and PTGIS may affect the risk of rectal cancer. In addition, this study suggests that current use of NSAIDs may modify associations between CRC risk and SNPs in ALOX5, PKN1, PTGER2, PTGER3, PTGER4, and TBXAS1. These findings may aid in the development of genetically targeted cancer prevention strategies with NSAIDs.

Citation Format: Alexa J. Resler, Laura Heath, Karen W. Makar, John Whitton, Nina Habermann, Hansong Wang, Polly A. Newcomb, Loic LeMarchand, John D. Potter, Cornelia M. Ulrich. Genetic variation in prostaglandin synthesis and related pathways, NSAID use, and risk of colorectal cancer in the Colon Cancer Family Registry. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 37.