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Updated: Jul 3, 2026
Cell-Free DNA Integrity Analysis in Urine Samples
Published on: January 5, 2017
Analysis of variants in DNA damage signalling genes in bladder cancer
Ananya Choudhury1, Faye Elliott, Mark M Iles
1Cancer Research UK Clinical Centre, Section of Oncology, Leeds Institute of Molecular Medicine, Leeds, LS9 7TF, UK. ananya@doctors.org.uk
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.
Insights
Single nucleotide polymorphisms (SNPs) in DNA double-strand break (DSB) signaling genes do not appear to significantly increase bladder cancer risk. This study found no strong evidence linking these genetic variations to bladder cancer predisposition or environmental exposure effects.
Area of Science:
- Genetics and Cancer Epidemiology
- Molecular Biology and DNA Repair Mechanisms
- Environmental Health and Occupational Exposures
Background:
- Occupational chemical exposure and cigarette smoke components can induce DNA damage in bladder urothelium.
- Defective DNA repair can lead to mutations, genetic instability, and bladder cancer development.
- DNA damage signaling acts as a tumor suppressor in early bladder lesions, but this function is lost during cancer progression.
Purpose of the Study:
- To investigate the hypothesis that single nucleotide polymorphisms (SNPs) in DNA double-strand break (DSB) signaling genes influence bladder cancer predisposition.
- To determine if these genetic variations modulate the impact of environmental exposures, such as smoking and occupational dye exposure, on bladder cancer risk.
Main Methods:
- A case-control study involving 771 bladder cancer cases and 800 controls.
- Genotyping of 24 SNPs in key DSB signaling genes (MRE11, NBS1, RAD50, H2AX, ATM) using Taqman allelic discrimination.
- Interviews collected data on smoking habits and occupational history; logistic regression adjusted for confounders.
Main Results:
- Smoking and occupational dye exposure were significantly associated with increased bladder cancer risk.
- A marginal association was observed for one MRE11 3'UTR SNP (rs2155209) with bladder cancer risk in individuals homozygous for the rare allele.
- No other tested SNPs showed a significant association with bladder cancer, nor did any SNPs interact with smoking or dye exposure.
Conclusions:
- The study provides limited support for the hypothesis that SNPs in DSB signaling genes influence bladder cancer predisposition.
- Apart from a potential marginal effect of one MRE11 SNP, the investigated genetic variations do not appear to be major modulators of bladder cancer risk.
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