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Open Access Research article

Analysis of variants in DNA damage signalling genes in bladder cancer

Ananya Choudhury1, Faye Elliott2, Mark M Iles2, Michael Churchman3, Robert G Bristow4, D Timothy Bishop2 and Anne E Kiltie1*

Author Affiliations

1 Cancer Research UK Clinical Centre, Section of Oncology, Leeds Institute of Molecular Medicine, Leeds, LS9 7TF, UK

2 Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, LS9 7TF, UK

3 CR-UK Genotyping Facility, University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, UK

4 Ontario Cancer Institute, Princess Margaret Hospital, Toronto, M5G 2M9, Canada

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BMC Medical Genetics 2008, 9:69  doi:10.1186/1471-2350-9-69

Published: 18 July 2008

Abstract

Background

Chemicals from occupational exposure and components of cigarette smoke can cause DNA damage in bladder urothelium. Failure to repair DNA damage by DNA repair proteins may result in mutations leading to genetic instability and the development of bladder cancer. Immunohistochemistry studies have shown DNA damage signal activation in precancerous bladder lesions which is lost on progression, suggesting that the damage signalling mechanism acts as a brake to further tumorigenesis. Single nucleotide polymorphisms (SNPs) in DSB signalling genes may alter protein function. We hypothesized that SNPs in DSB signalling genes may modulate predisposition to bladder cancer and influence the effects of environmental exposures.

Methods

We recruited 771 cases and 800 controls (573 hospital-based and 227 population-based from a previous case-control study) and interviewed them regarding their smoking habits and occupational history. DNA was extracted from a peripheral blood sample and genotyping of 24 SNPs in MRE11, NBS1, RAD50, H2AX and ATM was undertaken using an allelic discrimination method (Taqman).

Results

Smoking and occupational dye exposure were strongly associated with bladder cancer risk. Using logistic regression adjusting for age, sex, smoking and occupational dye exposure, there was a marginal increase in risk of bladder cancer for an MRE11 3'UTR SNP (rs2155209, adjusted odds ratio 1.54 95% CI (1.13–2.08, p = 0.01) for individuals homozygous for the rare allele compared to those carrying the common homozygous or heterozygous genotype). However, in the hospital-based controls, the genotype distribution for this SNP deviated from Hardy-Weinberg equilibrium. None of the other SNPs showed an association with bladder cancer and we did not find any significant interaction between any of these polymorphisms and exposure to smoking or dye exposure.

Conclusion

Apart from a possible effect for one MRE11 3'UTR SNP, our study does not support the hypothesis that SNPs in DSB signaling genes modulate predisposition to bladder cancer.