DNA-Repair Genetic Polymorphisms and Breast Cancer Risk

Tasha R. Smith, Edward A. Levine, Nancy D. Perrier, Mark Steven Miller, Rita I. Freimanis, Kurt Lohman, L. Douglas Case, Jianfeng Xu, Harvey W. Mohrenweiser, Jennifer J. Hu

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

Mammalian cells are constantly exposed to genotoxic agents from both endogenous and exogenous sources. Genetic variability in DNA repair contributes to deficient repair and breast cancer risk. Using samples collected in an ongoing, clinic-based, case-control study (253 cases and 268 controls), we tested whether breast cancer risk is associated with four amino acid substitution variants in three DNA repair genes, including XRCC1 Arg194Trp and XRCC1 Arg399Gln in base excision repair, XRCC3 Thr241Met in homologous recombination repair, and ERCC4/XPF Arg415Gln in nucleotide excision repair. Carriers of at least one variant allele of XRCC1 Arg194Trp [Arg/Trp and Trp/Trp versus Arg/Arg, odds ratio (OR) = 1.60, 95% confidence interval (CI) = 0.89-2.87] or two variant alleles of XRCC3 241Met/Met may have an increased risk of breast cancer (Met/Met versus Thr/Thr and Thr/Met, OR = 1.54, 95% CI = 0.94-2.52). No association between XRCC1 Arg399Gln genotype and breast cancer risk was observed. The genotype distribution of ERCC4/XPF Arg415Gln differed significantly between cases and controls (P = 0.02), and the ERCC4/XPF 415Gln/Gln genotype was found in only seven cases (3%) but not in controls. In addition, breast cancer risk was significantly associated with an increasing number of combined variant alleles of XRCC1 Arg194Trp, XRCC3 Thr241Met, and ERCC4/XPF Arg415Gln in a four-level model (Ptrend = 0.04): OR = 1.0 for those without a variant allele (referent group); OR = 1.04 (95% CI = 0.67-1.61) for those with one variant allele; OR = 1.38 (95% CI = 0.83-2.29) for those with two variant alleles; and age-adjusted OR = 2.60 (95% CI = 1.03-6.59) for those with three or more variant alleles after adjustment for age, family history, age at menarche, age at first live birth, and body mass index. We provide evidence that variants of XRCC1, XRCC3, and ERCC4/XPF genes, particularly in combination, contribute to breast cancer susceptibility.

Original languageEnglish (US)
Pages (from-to)1200-1204
Number of pages5
JournalCancer Epidemiology Biomarkers and Prevention
Volume12
Issue number11 II
StatePublished - Nov 2003

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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