title: Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk.
abstract: Previous research demonstrates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage (e.g. chromosomal aberrations) with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide exposure and 324 single-nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1444 male controls in a nested case-control study of white Agricultural Health Study pesticide applicators. We determined interaction P values using likelihood ratio tests from logistic regression models and three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score. We adjusted for multiple comparisons using the false discovery rate (FDR) method. Of the 17 interactions that met FDR <0.2, 3 displayed a monotonic increase in prostate cancer risk with increasing exposure in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.65-5.39; P(interact) = 3.6 × 10(-4); FDR-adjusted P = 0.11]. Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r(2) = 1.0), exhibited increased risk with high versus no carbofuran use (OR 2.01; 95% CI 1.31-3.10 for rs11744596; P(interact) = 7.2 × 10(-4); FDR-adjusted P = 0.09). In contrast, we did not observe associations among men with other genotypes at these loci. While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20892-7240, USA. barrykh@mail.nih.gov
authors.forename: Kathryn Hughes
authors.initials: KH
authors.lastname: Barry
authors.forename: Stella
authors.initials: S
authors.lastname: Koutros
authors.forename: Gabriella
authors.initials: G
authors.lastname: Andreotti
authors.forename: Dale P
authors.initials: DP
authors.lastname: Sandler
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Burdette
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Laura E
authors.initials: LE
authors.lastname: Beane Freeman
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lubin
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ma
authors.forename: Tongzhang
authors.initials: T
authors.lastname: Zheng
authors.forename: Michael C R
authors.initials: MC
authors.lastname: Alavanja
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D004260:DNA Repair; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010575:Pesticides / Q000506:poisoning*; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D012307:Risk Factors
chemical_list: D010575:Pesticides
references.citation: Mutat Res. 2003 Jun;543(3):251-72
references.pmid: 12787816
references.citation: Am J Ind Med. 1997 Feb;31(2):233-42
references.pmid: 9028440
references.citation: Epidemiology. 2002 Jan;13(1):94-9
references.pmid: 11805592
references.citation: Can Fam Physician. 2007 Oct;53(10):1712-20
references.pmid: 17934035
references.citation: Environ Sci Technol. 2009 Aug 15;43(16):6370-7
references.pmid: 19746739
references.citation: J Expo Anal Environ Epidemiol. 2002 Sep;12(5):313-8
references.pmid: 12198579
references.citation: Cancer Lett. 2005 Apr 8;220(2):125-35
references.pmid: 15766587
references.citation: Environ Health Perspect. 1996 Apr;104(4):362-9
references.pmid: 8732939
references.citation: Mutagenesis. 2003 Mar;18(2):201-5
references.pmid: 12621077
references.citation: J Agromedicine. 2009;14(2):206-14
references.pmid: 19437279
references.citation: Environ Health Perspect. 2010 Aug;118(8):1117-25
references.pmid: 20444670
references.citation: Cancer Res. 2004 Feb 1;64(3):1197-201
references.pmid: 14871857
references.citation: Hum Exp Toxicol. 2005 Sep;24(9):439-45
references.pmid: 16235732
references.citation: Mutat Res. 1983 Mar;116(3-4):185-216
references.pmid: 6339892
references.citation: Mutagenesis. 1998 Mar;13(2):157-66
references.pmid: 9568589
references.citation: J Occup Environ Med. 2010 Nov;52(11):1098-105
references.pmid: 21063187
references.citation: Toxicology. 2001 Dec 14;169(2):153-61
references.pmid: 11718956
references.citation: Science. 2001 Feb 16;291(5507):1284-9
references.pmid: 11181991
references.citation: Food Chem Toxicol. 2007 Dec;45(12):2488-98
references.pmid: 17673351
references.citation: Nat Genet. 2008 Mar;40(3):310-5
references.pmid: 18264096
references.citation: Ecotoxicology. 2003 Feb-Aug;12(1-4):345-63
references.pmid: 12739880
references.citation: Mutat Res. 2000 Feb 16;465(1-2):123-9
references.pmid: 10708977
references.citation: Am J Hum Genet. 2004 Jan;74(1):106-20
references.pmid: 14681826
references.citation: Mutat Res. 2005 Sep 4;577(1-2):275-83
references.pmid: 15922366
references.citation: Mutat Res. 1998 Aug 7;416(1-2):101-13
references.pmid: 9725996
references.citation: Mutat Res. 2008 Jul 31;654(2):168-75
references.pmid: 18603015
references.citation: Ann Occup Hyg. 2002 Mar;46(2):245-60
references.pmid: 12074034
references.citation: Environ Mol Mutagen. 2009 Jan;50(1):37-45
references.pmid: 19031420
references.citation: Int Arch Occup Environ Health. 2004 Nov;77(8):559-70
references.pmid: 15688248
references.citation: Cancer Res. 1998 Sep 15;58(18):4117-21
references.pmid: 9751622
references.citation: Environ Health Perspect. 2011 Dec;119(12):1726-32
references.pmid: 21810555
references.citation: Cancer Causes Control. 2006 May;17(4):353-73
references.pmid: 16596288
references.citation: Cancer Res. 2010 Nov 15;70(22):9224-33
references.pmid: 20978189
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: Environ Health Perspect. 2006 Dec;114(12):1838-42
references.pmid: 17185272
references.citation: Mutat Res. 1982 Mar;101(1):19-29
references.pmid: 7043246
references.citation: Mutat Res. 1986 Nov;168(3):301-25
references.pmid: 3796654
references.citation: Exp Cell Res. 1988 Mar;175(1):184-91
references.pmid: 3345800
references.citation: Nat Genet. 2008 Mar;40(3):316-21
references.pmid: 18264097
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: J Expo Sci Environ Epidemiol. 2010 Sep;20(6):559-69
references.pmid: 19888312
references.citation: Methods Mol Biol. 2009;471:361-85
references.pmid: 19109789
references.citation: J Biol Chem. 1999 Jun 25;274(26):18173-80
references.pmid: 10373416
references.citation: Cancer Epidemiol Biomarkers Prev. 2002 May;11(5):493-6
references.pmid: 12010865
references.citation: Am J Epidemiol. 2003 May 1;157(9):800-14
references.pmid: 12727674