TY - JOUR
T1 - NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer
T2 - Results from the Spanish Bladder Cancer Study and meta-analyses
AU - García-Closas, Montserrat
AU - Malats, Núria
AU - Silverman, Debra
AU - Dosemeci, Mustafa
AU - Kogevinas, Manolis
AU - Hein, David W.
AU - Tardón, Adonina
AU - Serra, Consol
AU - Carrato, Alfredo
AU - García-Closas, Reina
AU - Lloreta, Josep
AU - Castaño-Vinyals, Gemma
AU - Yeager, Meredith
AU - Welch, Robert
AU - Chanock, Stephen
AU - Chatterjee, Nilanjan
AU - Wacholder, Sholom
AU - Samanic, Claudine
AU - Torà, Montserrat
AU - Fernández, Francisco
AU - Real, Francisco X.
AU - Rothman, Nathaniel
N1 - Funding Information:
We thank Robert C Saal (Westat, Rockville, MD, USA), Leslie Carroll, and Jane Wang (both IMS, Silver Spring, MD, USA) for their support in study and data management; Maria Sala (Institut Municipal d'Investigació Mèdica, Barcelona, Spain) for her work in data collection; physicians, nurses, interviewers, and study participants for their efforts during fieldwork; Pam Marcus and Larry Engel from the National Cancer Institute for providing datasets for meta-analyses used in their previous publications; and the Genetic Susceptibility to Environmental Carcinogens Study ( http://www.gsec.net/ ) for bringing together the collaborative network of investigators that contributed data used in Engel and colleagues' study, 8 which enabled the update of the meta-analysis on GSTM1 , smoking, and bladder cancer. This work was supported by National Cancer Institute Westat contract number N02-CP-11015, FIS/Spain 00/0745 and G03/174, and CA34627.
PY - 2005/8/20
Y1 - 2005/8/20
N2 - Background: Many reported associations between common genetic polymorphisms and complex diseases have not been confirmed in subsequent studies. An exception could be the association between NAT2 slow acetylation, GSTM1 null genotype, and bladder-cancer risk. However, current evidence is based on meta-analyses of relatively small studies (range 23-374 cases) with some evidence of publication bias and study heterogeneity. Associations between polymorphisms in other NAT and GST genes and bladder-cancer risk have been inconsistent. Methods: We investigated polymorphisms in NAT2, GSTM1, NAT1, GSTT1, GSTM3, and GSTP1 in 1150 patients with transitional-cell carcinoma of the urinary bladder and 1149 controls in Spain; all the participants were white. We also carried out meta-analyses of NAT2, GSTM1, and bladder cancer that included more than twice as many cases as in previous reports. Findings: In our study, the odds ratios for bladder cancer for individuals with deletion of one or two copies of the GSTM1 gene were 1.2 (95% CI 0.8-1.7) and 1.9 (1.4-2.7) respectively (p for trend <0.0001). Compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (1.4 [1.2-1.7]) that was stronger for cigarette smokers than for never smokers (p for interaction 0.008). No significant associations were found with the other polymorphisms. Meta-analyses showed that the overall association for NAT2 was robust (p<0.0001), and case-only meta-analyses provided support for an interaction between NAT2 and smoking (p for interaction 0.009). The overall association for GSTM1 was also robust (p<0.0001) and was not modified by smoking status (p=0.86). Interpretation: The GSTM1 null genotype increases the overall risk of bladder cancer, and the NAT2 slow-acetylator genotype increases risk particularly among cigarette smokers. These findings provide compelling evidence for the role of common polymorphisms in the aetiology of cancer. Relevance to practice: Although the relative risks are modest, these polymorphisms could account for up to 31% of bladder cancers because of their high prevalence.
AB - Background: Many reported associations between common genetic polymorphisms and complex diseases have not been confirmed in subsequent studies. An exception could be the association between NAT2 slow acetylation, GSTM1 null genotype, and bladder-cancer risk. However, current evidence is based on meta-analyses of relatively small studies (range 23-374 cases) with some evidence of publication bias and study heterogeneity. Associations between polymorphisms in other NAT and GST genes and bladder-cancer risk have been inconsistent. Methods: We investigated polymorphisms in NAT2, GSTM1, NAT1, GSTT1, GSTM3, and GSTP1 in 1150 patients with transitional-cell carcinoma of the urinary bladder and 1149 controls in Spain; all the participants were white. We also carried out meta-analyses of NAT2, GSTM1, and bladder cancer that included more than twice as many cases as in previous reports. Findings: In our study, the odds ratios for bladder cancer for individuals with deletion of one or two copies of the GSTM1 gene were 1.2 (95% CI 0.8-1.7) and 1.9 (1.4-2.7) respectively (p for trend <0.0001). Compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (1.4 [1.2-1.7]) that was stronger for cigarette smokers than for never smokers (p for interaction 0.008). No significant associations were found with the other polymorphisms. Meta-analyses showed that the overall association for NAT2 was robust (p<0.0001), and case-only meta-analyses provided support for an interaction between NAT2 and smoking (p for interaction 0.009). The overall association for GSTM1 was also robust (p<0.0001) and was not modified by smoking status (p=0.86). Interpretation: The GSTM1 null genotype increases the overall risk of bladder cancer, and the NAT2 slow-acetylator genotype increases risk particularly among cigarette smokers. These findings provide compelling evidence for the role of common polymorphisms in the aetiology of cancer. Relevance to practice: Although the relative risks are modest, these polymorphisms could account for up to 31% of bladder cancers because of their high prevalence.
UR - http://www.scopus.com/inward/record.url?scp=23844512858&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=23844512858&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(05)67137-1
DO - 10.1016/S0140-6736(05)67137-1
M3 - Article
C2 - 16112301
AN - SCOPUS:23844512858
SN - 0140-6736
VL - 366
SP - 649
EP - 659
JO - Lancet
JF - Lancet
IS - 9486
ER -