Journal Article

Bladder cancer risk and genetic variation in <i>AKR1C3</i> and other metabolizing genes

Jonine D. Figueroa, Núria Malats, Montserrat García-Closas, Francisco X. Real, Debra Silverman, Manolis Kogevinas, Stephen Chanock, Robert Welch, Mustafa Dosemeci, Qing Lan, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina García-Closas, Gemma Castaño-Vinyals and Nathaniel Rothman

in Carcinogenesis

Volume 29, issue 10, pages 1955-1962
Published in print October 2008 | ISSN: 0143-3334
Published online July 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn163
Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes

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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.

Journal Article.  5106 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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