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Carcinogenesis Advance Access originally published online on July 16, 2008
Carcinogenesis 2008 29(10):1955-1962; 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 Malats2,11, Montserrat García-Closas1, Francisco X. Real3,4,11, Debra Silverman1, Manolis Kogevinas2,5, Stephen Chanock1,7, Robert Welch7,{dagger}, Mustafa Dosemeci1, Qing Lan1, Adonina Tardón8, Consol Serra4, Alfredo Carrato9, Reina García-Closas10, Gemma Castaño-Vinyals2,3,6 and Nathaniel Rothman1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, MD, USA
2 Center for Research in Environmental Epidemiology, Barcelona, Spain
3 Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigació Mèdica, Barcelona, Spain
4 Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
5 Medical School, Heraklion, Greece
6 Centro de Investigación Biomédica en Red Epidemiology and Public Health, Spain
7 Core Genotype Facility, Advanced Technology Center, National Cancer Institute, Gaithersberg, MD, USA
8 Universidad de Oviedo, Oviedo, Spain
9 Department of Medical Oncology, Elche University Hospital, Elche, Spain
10 Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain
11 Present address: Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029 Madrid, Spain

* To whom correspondence should be addressed. Tel: +301 402 3654; Fax: +301 402 0916;Email: figueroaj{at}mail.nih.gov

Aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) 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 [aryl hydrocarbon receptor (AHR), AHRR and aryl hydrocarbon nuclear translocator (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 1150 cases of urothelial carcinomas and 1149 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 observed 10 non-redundant single-nucleotide polymorphisms (SNPs) in five genes (AKR1C3, ARNT, CYP1A1, CYP1B1 and SULT1A2) significantly associated with bladder cancer risk. We observed an inverse association with risk for the AKR1C3 promoter SNP rs1937845 [OR (95% CI) for heterozygote and homozygote variant compared with common homozygote genotype were 0.86 (0.70–1.06) 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. Analysis of 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.

Abbreviations: AA, aromatic amine; AHR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon nuclear translocator; AKR, aldo–keto reductase; CART, classification trees; CEU, Utah residents with ancestry from northern and western Europe; CI, confidence interval; CYP, cytochrome P450; FDR, false discovery rate; NQO1, NAD(P)H dehydrogenase, quinone 1; OR, odds ratio; PAH, polycyclic aromatic hydrocarbon; SNP, single-nucleotide polymorphism

{dagger} The author has deceased.

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


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