title: DNA repair gene variants in relation to overall cancer risk: a population-based study.
abstract: The hypothesis that germ-line polymorphisms in DNA repair genes influence cancer risk has previously been tested primarily on a cancer site-specific basis. The purpose of this study was to test the hypothesis that DNA repair gene allelic variants contribute to globally elevated cancer risk by measuring associations with risk of all cancers that occurred within a population-based cohort. In the CLUE II cohort study established in 1989 in Washington County, MD, this study was comprised of all 3619 cancer cases ascertained through 2007 compared with a sample of 2296 with no cancer. Associations were measured between 759 DNA repair gene single nucleotide polymorphisms (SNPs) and risk of all cancers. A SNP in O(6)-methylguanine-DNA methyltransferase, MGMT, (rs2296675) was significantly associated with overall cancer risk [per minor allele odds ratio (OR) 1.30, 95% confidence interval (CI) 1.19-1.43 and P-value: 4.1 × 10(-8)]. The association between rs2296675 and cancer risk was stronger among those aged ≤54 years old than those who were ≥55 years at baseline (P-for-(interaction) = 0.021). OR were in the direction of increased risk for all 15 categories of malignancies studied (P < 0.0001), ranging from 1.22 (P = 0.42) for ovarian cancer to 2.01 (P = 0.008) for urinary tract cancers; the smallest P-value was for breast cancer (OR 1.45, P = 0.0002). The results indicate that the minor allele of MGMT SNP rs2296675, a common genetic marker with 37% carriers, was significantly associated with increased risk of cancer across multiple tissues. Replication is needed to more definitively determine the scientific and public health significance of this observed association.
authors.affiliation: Hollings Cancer Center and Division of Epidemiology and Biostatistics, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA. alberg@musc.edu
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Alberg
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Jorgensen
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.forename: Lee
authors.initials: L
authors.lastname: Wheless
authors.forename: Yin Yao
authors.initials: YY
authors.lastname: Shugart
authors.forename: Yvette
authors.initials: Y
authors.lastname: Berthier-Schaad
authors.forename: Bailey
authors.initials: B
authors.lastname: Kessing
authors.forename: Judith
authors.initials: J
authors.lastname: Hoffman-Bolton
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Helzlsouer
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Lesley
authors.initials: L
authors.lastname: Francis
authors.forename: Rhoda M
authors.initials: RM
authors.lastname: Alani
authors.forename: Michael W
authors.initials: MW
authors.lastname: Smith
authors.forename: Paul T
authors.initials: PT
authors.lastname: Strickland
mesh_terms: D000328:Adult; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008396:Maryland / Q000453:epidemiology; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics*; D011159:Population Surveillance; D012307:Risk Factors