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Carcinogenesis Advance Access originally published online on June 8, 2007
Carcinogenesis 2007 28(8):1788-1793; doi:10.1093/carcin/bgm132
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Published by Oxford University Press 2007.

Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk

Jonine D. Figueroa1,*, Núria Malats2, Nathaniel Rothman1, Francisco X. Real3, Debra Silverman1, Manolis Kogevinas2,5, Stephen Chanock1,6,10, Meredith Yeager6, Robert Welch6, Mustafa Dosemeci1, Adonina Tardón7, Consol Serra4, Alfredo Carrato8, Reina García-Closas9, Gemma Castaño-Vinyals2 and Montserrat García-Closas1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, MD, USA
2 Center for Research in Environmental Epidemiology, Barcelona, Spain
3 Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigació Mèdica, Barcelona, Spain
4 Universitat Pompeu Fabra, Barcelona, Spain
5 Medical School, Heraklion, Greece
6 Core Genotype Facility at the Advanced Technology Center of the National Cancer Institute, Gaithersburg, MD, USA
7 Universidad de Oviedo, Oviedo, Spain
8 Medical Oncology Department, Elche University Hospital, Elche, Spain
9 Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain
10 Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD, USA

* To whom correspondence should be addressed. Tel: 301 402 3654; Fax: 301 402 0916; Email: figueroaj{at}mail.nih.gov

The double-strand break DNA repair (DSBR) pathway is implicated in maintaining genomic stability and therefore could affect bladder cancer risk. Here we present data evaluating 39 single-nucleotide polymorphisms (SNPs) in seven candidate genes whose products are involved in DNA break sensing (NBS1, BRCA1 interacting genes BRIP1 and ZNF350), non-homologous end-joining (NHEJ) DNA repair (XRCC4) and homologous recombination (HR) repair (RAD51, XRCC2 and XRCC3). SNPs for RAD51 and XRCC2 covered most of the common variation. Associations with bladder cancer risk were evaluated in 1150 newly diagnosed cases of urinary bladder transitional cell carcinomas and 1149 controls conducted in Spain during 1997–2001. We found that the genetic variants evaluated significantly contributed to bladder cancer risk (global likelihood ratio test P = 0.01). Subjects with the ZNF350 R501S (rs2278415) variant allele showed significantly reduced risk compared with common homozygote variants, odds ratio (OR) [95% confidence interval (95% CI)]: 0.76 (0.62–0.93) per variant allele. Carriers of a putative functional SNP in intron 7 of XRCC4 (rs1805377) had significantly increased bladder cancer risk compared with common homozygotes: 1.33 (1.08–1.64) per variant allele. Lastly, XRCC2 homozygote variants for three promoter SNPs (rs10234749, rs6464268, rs3218373) and one non-synonymous SNP (rs3218536, R188H) were associated with reduced bladder cancer risk (ORs ranging from 0.36 to 0.50 compared with common homozygotes). Meta-analysis for XRCC3 T241M (rs861539) had a significant small increase in risk among homozygote variants: OR (95% CI) = 1.17 (1.00–1.36). Results from this study provide evidence for associations between variants in genes in the DSBR pathway and bladder cancers risk that warrant replication in other study populations.

Abbreviations: CI, confidence interval; DSB, double-strand break; DSBR, double-strand break DNA repair; FDR, false discovery rate; HR, homologous recombination; LRT, likelihood ratio test; NHEJ, non-homologous end joining; OR, odds ratio; SNP, single-nucleotide polymorphism

Received February 9, 2007; revised April 18, 2007; accepted May 25, 2007.


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