title: Smoking and polymorphisms in xenobiotic metabolism and DNA repair genes are additive risk factors affecting bladder cancer in Northern Tunisia.
abstract: Cancer epidemiology has undergone marked development since the nineteen-fifties. One of the most spectacular and specific contributions was the demonstration of the massive effect of smoking and genetic polymorphisms on the occurrence of bladder cancer. The tobacco carcinogens are metabolized by various xenobiotic metabolizing enzymes, such as the super-families of N-acetyltransferases (NAT) and glutathione S-transferases (GST). DNA repair is essential to an individual's ability to respond to damage caused by tobacco carcinogens. Alterations in DNA repair genes may affect cancer risk by influencing individual susceptibility to this environmental exposure. Polymorphisms in NAT2, GST and DNA repair genes alter the ability of these enzymes to metabolize carcinogens or to repair alterations caused by this process. We have conducted a case-control study to assess the role of smoking, slow NAT2 variants, GSTM1 and GSTT1 null, and XPC, XPD, XPG nucleotide excision-repair (NER) genotypes in bladder cancer development in North Tunisia. Taken alone, each gene unless NAT2 did not appear to be a factor affecting bladder cancer susceptibility. For the NAT2 slow acetylator genotypes, the NAT2*5/*7 diplotype was found to have a 7-fold increased risk to develop bladder cancer (OR = 7.14; 95% CI: 1.30-51.41). However, in tobacco consumers, we have shown that Null GSTM1, Wild GSTT1, Slow NAT2, XPC (CC) and XPG (CC) are genetic risk factors for the disease. When combined together in susceptible individuals compared to protected individuals these risk factors give an elevated OR (OR = 61). So, we have shown a strong cumulative effect of tobacco and different combinations of studied genetic risk factors which lead to a great susceptibility to bladder cancer.
authors.affiliation: Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University of El Tunis Manar I, 2092 Tunis, Tunisia. rouissik2000@yahoo.fr
authors.forename: Kamel
authors.initials: K
authors.lastname: Rouissi
authors.forename: Slah
authors.initials: S
authors.lastname: Ouerhani
authors.forename: Bechr
authors.initials: B
authors.lastname: Hamrita
authors.forename: Karim
authors.initials: K
authors.lastname: Bougatef
authors.forename: Raja
authors.initials: R
authors.lastname: Marrakchi
authors.forename: Mohamed
authors.initials: M
authors.lastname: Cherif
authors.forename: Mohamed Riadh
authors.initials: MR
authors.lastname: Ben Slama
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bouzouita
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chebil
authors.forename: Amel
authors.initials: A
authors.lastname: Ben Ammar Elgaaied
mesh_terms: D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D002273:Carcinogens / Q000378:metabolism; D016022:Case-Control Studies; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D004198:Disease Susceptibility; D004720:Endonucleases / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014416:Tunisia; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D001191:Arylamine N-Acetyltransferase; D002273:Carcinogens; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005982:Glutathione Transferase; D009687:Nuclear Proteins; D014157:Transcription Factors; D015262:Xenobiotics; D051759:Xeroderma Pigmentosum Group D Protein; D000099250:DNA Excision Repair Protein ERCC-5; C086984:XPC protein, human; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1; C497292:ERCC2 protein, human