Polymorphisms in DNA double-strand break repair genes and risk of breast cancer: two population-based studies in USA and Poland, and meta-analyses
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The double-strand break DNA repair pathway has been implicated in breast carcinogenesis. We evaluated the association between 19 polymorphisms in seven genes in this pathway (XRCC2, XRCC3, BRCA2, ZNF350, BRIP1, XRCC4, LIG4) and breast cancer risk in two population-based studies in USA (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). These data suggested weak associations with breast cancer risk for XRCC3 T241M and IVS7-14A>G (pooled odds ratio (95% confidence interval): 1.18 (1.04–1.34) and 0.85 (0.73–0.98) for homozygous variant vs wild-type genotypes, respectively), and for an uncommon variant in ZNF350 S472P (1.24 (1.05–1.48)), with no evidence for study heterogeneity. The remaining variants examined had no significant relationships to breast cancer risk. Meta-analyses of studies in Caucasian populations, including ours, provided some support for a weak association for homozygous variants for XRCC3 T241M (1.16 (1.04–1.30); total of 10,979 cases and 10,423 controls) and BRCA2 N372H (1.13 (1.10–1.28); total of 13,032 cases and 13,314 controls), and no support for XRCC2 R188H (1.06 (0.59–1.91); total of 8,394 cases and 8,404 controls). In conclusion, the genetic variants evaluated are unlikely to have a substantial overall association with breast cancer risk; however, weak associations are possible for XRCC3 (T241M and IVS7-14A>G), BRCA2 N372H, and ZNF350 S472P. Evaluation of potential underlying gene–gene interactions or associations in population subgroups will require even larger sample sizes.
KeywordsBreast Cancer Breast Cancer Risk Polish Study Polish Population Homozygous Variant
This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics and the Center for Cancer Research, and by RO1 CA67264, CA47147 (P. Newcomb), by RO1 CA67338, CA69664 (L. Titus-Ernstoff), and RO1 CA47305 (K. Egan). We thank Amy Trentham-Dietz and John Hampton (both from the Comprehensive Cancer Center and Department of Population Health Sciences of the University of Wisconsin, Madison, WI, USA) for their work in data and sample collection and management for the USA breast cancer study; Anita Soni (Westat, Rockville, MD, USA) for her work on study management for the Polish breast cancer study; Pei Chao (IMS, Silver Spring, MD, USA) for her work on data and sample management for both the USA and Polish breast cancer studies; and physicians, nurses, interviewers and study participants for their efforts during field work.
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