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Carcinogenesis Advance Access published online on July 16, 2008
Carcinogenesis, doi:10.1093/carcin/bgn163
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes

Jonine D. Figueroa1, Núria Malats2,*, Montserrat García-Closas1, Francisco X. Real3,4,*, Debra Silverman1, Manolis Kogevinas2,5, Stephen Chanock1,7, Robert Welch8, Mustafa Dosemeci1, Qing Lan1, Adonina Tardón9, Consol Serra4, Alfredo Carrato10, Reina García-Closas11, Gemma Castaño-Vinyals2,6 and Nathaniel Rothman1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, MD, United States of America
2 Center for Research in Environmental Epidemiology, Barcelona, Spain
3 Unitat de Biologia Cel.lular i Molecular, Institut Municipal d'Investigació Mèdica (IMIM), Barcelona, Spain
4 Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
5 Medical School, Heraklion, Greece
6 CIBER Epidemiology and Public Health, Spain
7 Core Genotype Facility at the Advanced Technology Center of the National Cancer Institute, Gaithersberg, MD
8 Core Genotype Facility at the Advanced Technology Center of the National Cancer Institute, Gaithersberg, MD, Deceased
9 Universidad de Oviedo, Oviedo, Spain
10 Medical Oncology Department, Elche University Hospital, Elche, Spain
11 Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain

Aromatic amines and polycyclic aromatic hydrocarbons are carcinogens present in tobacco smoke and functional polymorphisms in NAT2 and GSTM1 metabolizing genes are associated with increased bladder cancer risk. We evaluated whether genetic variation in other candidate metabolizing genes are also associated with risk. Candidates included genes that control the transcription of metabolizing genes (AHR, AHRR, and ARNT), and genes that activate/detoxify AA or PAH (AKR1C3, CYP1A1, CYP1A2, CYP1B1, CYP3A4, EPHX1, EPHX2, NQO1, MPO, UGT1A4, SULT1A1, and SULT1A2). Using genotype data from 1,150 cases of urothelial carcinomas and 1,149 controls from the Spanish Bladder Cancer Study, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, gender, region and smoking status. Based on a test for trend, we observe ten nonredundant SNPs in five genes (AKR1C3, ARNT, CYP1A1, CYP1B1 and SULT1A2) significantly associated with bladder cancer risk. The most significant finding we observed was an inverse association with risk for the AKR1C3 promoter SNP rs1937845 [OR (95%CI) for heterozygote and homozygote variant compared to common homozygote genotype were 0.86 (0.75-1.06) and 0.74 (0.57-0.96), respectively; p for trend = 0.02]. Interestingly, genetic variation in this region has been associated with lung, non-Hodgkin lymphoma, and prostate cancer risk. We further analyzed additional SNPs to capture most (~90%) of common genetic variation in AKR1C3 and haplotype walking analyses based on all AKR1C3 SNPs (n = 25) suggest two separate regions associated with bladder cancer risk. These results indicate that genetic variation in carcinogen metabolizing genes, particularly AKR1C3, could be associated with bladder cancer risk.

* Present address: Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029-Madrid Spain

Received April 8, 2008; revised June 30, 2008; accepted July 2, 2008.


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