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

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1

Cancer Prevention Program, Fred Hutchinson Cancer Research Center

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Seattle, WA 98109

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USA

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2

Department of Epidemiology and

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Department of Public Health Genetics, University of Washington

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Seattle, WA 98195

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USA

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Cancer Prevention Program, Fred Hutchinson Cancer Research Center

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Seattle, WA 98109

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USA

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Cancer Prevention Program, Fred Hutchinson Cancer Research Center

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Seattle, WA 98109

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USA

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Department of Epidemiology and

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Department of Public Health Genetics, University of Washington

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Seattle, WA 98195

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USA

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Cancer Prevention Program, Fred Hutchinson Cancer Research Center

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Seattle, WA 98109

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USA

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Cancer Prevention Program, Fred Hutchinson Cancer Research Center

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Seattle, WA 98109

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USA

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Department of Epidemiology and

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Centre for Public Health Research, Massey University

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Wellington 6140

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New Zealand

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Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School

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Boston, MA 02115

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USA

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Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases

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Heidelberg 69120

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Germany

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Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases

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Heidelberg 69120

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Germany

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Integrated Cancer Genomics Division, Translational Genomics Research Institute

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Phoenix, AZ 85004

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Cancer Epidemiology Program, University of Hawaii Cancer Center

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Honolulu, HI 96813

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Received:

02 September 2013

Revision received:

20 May 2014

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Alexa J. Resler, Karen W. Makar, Laura Heath, John Whitton, John D. Potter, Elizabeth M. Poole, Nina Habermann, Dominique Scherer, David Duggan, Hansong Wang, Noralane M. Lindor, Michael N. Passarelli, John A. Baron, Polly A. Newcomb, Loic Le Marchand, Cornelia M. Ulrich, Genetic variation in prostaglandin synthesis and related pathways, NSAID use and colorectal cancer risk in the Colon Cancer Family Registry, Carcinogenesis, Volume 35, Issue 9, September 2014, Pages 2121–2126, https://doi.org/10.1093/carcin/bgu119
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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 [ORhet/hzv = 1.87, 95% confidence interval (CI) = 1.19–2.95, P = 0.03] and rs45525634 in PTGER2 (ORhet/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 (ORhet = 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.

© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Topic:

• prostaglandins
• polymorphism
• colorectal cancer
• anti-inflammatory agents, non-steroidal
• genotype
• heterozygote
• homozygote
• introns
• single nucleotide polymorphism
• relationship - sibling
• european continental ancestry group
• genetics
• rectal carcinoma
• candidate disease gene

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