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Genetic Polymorphisms in Base-Excision Repair Pathway Genes and Risk of Breast Cancer

Yawei Zhang^1,2, Polly A. Newcomb^3,4, Kathleen M. Egan⁵, Linda Titus-Ernstoff⁶, Stephen Chanock⁷, Robert Welch⁷, Louise A. Brinton¹, Jolanta Lissowska^1,8, Alicja Bardin-Mikolajczak⁸, Beata Peplonska^1,9, Neonila Szeszenia-Dbrowska⁹, Witold Zatonski⁸ and Montserrat Garcia-Closas¹

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Rockville, Maryland; ² Yale University School of Medicine, New Haven, Connecticut; ³ Cancer Prevention Research Group, Fred Hutchinson Cancer Research Center, Seattle, Washington; ⁴ Comprehensive Cancer Center and Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin; ⁵ Vanderbilt University Medical Center, Nashville, Tennessee; ⁶ Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hampshire; ⁷ Core Genotyping Facility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Gaithersburg, Maryland; ⁸ Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Institute of Oncology and Cancer Center, Warsaw, Poland; and ⁹ Nofer Institute of Occupational Medicine, Lodz, Poland

Requests for reprints: Yawei Zhang, School of Epidemiology and Public Health, Yale University, 60 College Street, LEPH 440, New Haven, CT 06520. Phone: 203-785-6210; Fax: 203-737-6023. E-mail: yawei.zhang{at}yale.edu or Montserrat García-Closas, Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Room 7076, 6120 Executive Boulevard, MSC 7234, Rockville, MD 20852-7234. Phone: 301-435-3981; Fax: 301-402-0916. E-mail: montse{at}nih.gov

Impaired base-excision repair (BER) function can give rise to the accumulation of DNA damage and initiation of cancer. We evaluated whether genetic variation in six BER pathway genes (XRCC1, ADPRT, APEX1, OGG1, LIG3, and MUTYH) is associated with breast cancer risk in two large population-based case-control studies in the United States (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). A detailed evaluation was first done in a subset of 1,898 cases and 1,514 controls with mouthwash DNA samples in the U.S. study. Significant findings were followed up in the remainder of the U.S. study population that provided cytobrush DNA samples and in the Polish study. Using data from U.S. study participants with mouthwash DNA, we found no significant overall association between breast cancer risk and XRCC1 R280H and R194W, ADPRT V726W, APEX1 D148E, OGG1 S326C, LIG3 R780H, or MUTYH 5' untranslated region. These data suggested a decreased risk for XRCC1Q399R homozygous variants compared with homozygous wild-type in premenopausal women, but these findings were not confirmed when data from cytobrush DNA samples were added [combined odds ratio (OR), 0.8; 95% confidence interval (95% CI), 0.6-1.1] or in the Polish study (OR, 1.0; 95% CI, 0.7-1.5). Meta-analyses based on our data and published data from studies of two single nucleotide polymorphisms in XRCC1 showed no evidence of an overall association between breast cancer risk and homozygous variants versus wild-type for Q399R (OR, 1.1; 95% CI, 1.0-1.2) or R194W (OR, 1.0; 95% CI, 0.7-1.8), although there was a suggestion for an association in Asian populations for Q399R (OR, 1.6; 95% CI, 1.1-2.4; P = 0.02). In conclusion, our results do not support that the polymorphisms evaluated in six BER pathway genes play a major role in breast carcinogenesis, particularly in Caucasian populations. (Cancer Epidemiol Biomarkers Prev 2006;15(2):353–8)

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