Carcinogenesis Advance Access published online on February 23, 2009
Carcinogenesis, doi:10.1093/carcin/bgp046
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Genetic polymorphisms in 85 DNA repair genes and bladder cancer risk
1 Institut Gustave Roussy, Department of Biostatistics and Epidemiology, Villejuif, France
2 Université Paris-Sud, CNRS, FRE2939, Institut Gustave Roussy, Villejuif, France
3 Institut Mutualiste Montsouris, Department of Urology, Paris, France
4 Hôpital Necker, Department of Urology, Paris, France
5 Hôpital Saint-Louis, Department of Urology, Paris, France
6 Centre National de Génotypage, Evry, France
7 INSERM, U794, Fondation Jean-Dausset – CEPH, Paris, France
Correspondence should be addressed to: Dr Simone BENHAMOU, INSERM U794, Fondation Jean Dausset – CEPH, 27 rue Juliette Dodu, 75010 Paris, Phone: (+33) 1 42114139, Fax: (+33) 1 42115315, Email: simone.benhamou{at}inserm.fr
Several defense mechanisms have been developed and maintained during the evolution to protect human cells against damage produced from exogenous or endogenous sources. We examined the associations between bladder cancer and a panel of 652 polymorphisms from 85 genes involved in maintenance of genetic stability (Base Excision Repair, Nucleotide Excision Repair, Double Strand Break Repair, and MisMatch Repair, as well as DNA synthesis and cell cycle regulation pathways) in 201 incident bladder cancer cases and 326 hospital controls. Score statistics were used to test differences in haplotype frequencies between cases and controls in an unconditional logistic regression model. To account for multiple testing, we associated to each p-value the expected proportion of false discoveries (q-value). Haplotype-analysis revealed significant associations (p<0.01) between bladder cancer and 2 genes (POLB and FANCA) with an associated q-value of 24%. A permutation test was also used to determine whether, in each pathway analyzed, there are more variants whose allelic frequencies are different between cases and controls as compared to what would be expected by chance. Differences were found for cell-cycle regulation (p = 0.02) and to a lesser extent for DSB repair (p = 0.05) pathways. These results hint to a few potential candidate genes; however, our study was limited by the small sample size and therefore low statistical power to detect associations. It is anticipated that genome-wide association studies will open new perspectives for interpretation of the results of extensive candidate gene studies such as ours.
Key Words: Gene polymorphisms • DNA repair • bladder cancer • epidemiology • smoking
This work was supported by the Ligue Contre le Cancer du Val-de-Marne, the Fondation de France, the Groupement d'Entreprises Françaises dans la Lutte contre le Cancer, and the Association pour la Recherche sur le Cancer, France.
Received December 16, 2008; revised February 10, 2009; accepted February 18, 2009.