title: Genetic variation in prostaglandin synthesis and related pathways, NSAID use and colorectal cancer risk in the Colon Cancer Family Registry.
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.
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Department of Epidemiology and, Department of Public Health Genetics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Alexa J
authors.initials: AJ
authors.lastname: Resler
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Department of Epidemiology and, Department of Public Health Genetics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Heath
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: John
authors.initials: J
authors.lastname: Whitton
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Department of Epidemiology and, Centre for Public Health Research, Massey University, Wellington 6140, New Zealand.
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.affiliation: Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg 69120, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Habermann
authors.affiliation: Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg 69120, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Scherer
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Hansong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Department of Epidemiology and, Department of Public Health Genetics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Passarelli
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA and.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Department of Epidemiology and.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Department of Epidemiology and, Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg 69120, Germany, German Cancer Consortium (DKTK), 69120 Heidelberg, Germany neli.ulrich@nct-heidelberg.de.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D053898:Biosynthetic Pathways / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000517:prevention & control; D005260:Female; D005787:Gene Frequency; D052138:Genes, Neoplasm; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011453:Prostaglandins / Q000096:biosynthesis; D012042:Registries; D012307:Risk Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D011453:Prostaglandins