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Genetic Susceptibility to Renal Cell Carcinoma: The Role of DNA Double-Strand Break Repair Pathway

Departments of ¹ Urology and ² Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Xifeng Wu, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Unit 1340, 1155 Hermann Pressler Boulevard, Houston, TX 77030. Phone: 713-745-2485; Fax: 713-792-4657. E-mail: xwu{at}mdanderson.org

Alterations in DNA repair genes have been shown to cause a reduction in host DNA repair capacity and may influence host susceptibility to carcinogenesis. The double-strand break repair is a major DNA-repair pathway. This study tested the hypothesis that common sequence variants of the double-strand break pathway genes predispose susceptible individuals to an increased risk for renal cell carcinoma. Toward this end, we evaluated the associations of 13 single-nucleotide polymorphisms in 10 candidate genes involved in the double-strand break pathway with renal cell carcinoma risk in a population-based case-control study that included 326 Caucasian renal cell carcinoma patients and 335 controls. Using the homozygous wild type as the reference group, we observed a significantly increased renal cell carcinoma risk associated with the homozygous variant genotype of NBS1 (rs1805794; odds ratio, 2.13; 95% confidence interval (95% CI), 1.17-3.86). Carrying of at least one copy of the variant XRCC4 allele was also associated with a significantly increased risk (rs1805377; odds ratio, 1.56; 95% CI, 1.08-2.26). Importantly, in pathway analysis, compared with the reference group (1 or less adverse alleles), individuals with two (odds ratio, 1.26; 95% CI, 0.83-1.91), three (odds ratio, 1.00; 95% CI, 0.64-1.56), and more than three adverse alleles (odds ratio, 1.75; 95% CI, 1.03-2.98) were at increased risk for renal cell carcinoma with significant association in subjects carrying more than 3 adverse alleles. Results from this study provide evidence that individuals with a higher number of genetic variations in the DBS repair pathway are at an increased risk for renal cell carcinoma. These findings require further validation in independent populations. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2366–73)