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

Abstract

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 (approximately 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.

• Authors: 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, Nathaniel Rothman
• Journal: Carcinogenesis (Carcinogenesis) Vol. 29 Issue 10 Pg. 1955-62 (Oct 2008) ISSN: 1460-2180 [Electronic] England
• PMID: 18632753 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ARNT protein, human
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Cytochrome P-450 Enzyme System
• 3-Hydroxysteroid Dehydrogenases
• Hydroxyprostaglandin Dehydrogenases
• AKR1C3 protein, human
• Aldo-Keto Reductase Family 1 Member C3
• Aryl Hydrocarbon Hydroxylases
• CYP1B1 protein, human
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP1B1
• Glutathione Transferase
• glutathione S-transferase M1

Topics

• 3-Hydroxysteroid Dehydrogenases (genetics)
• Adult
• Aged
• Aged, 80 and over
• Aldo-Keto Reductase Family 1 Member C3
• Aryl Hydrocarbon Hydroxylases
• Aryl Hydrocarbon Receptor Nuclear Translocator (genetics)
• Cytochrome P-450 CYP1A1 (genetics)
• Cytochrome P-450 CYP1B1
• Cytochrome P-450 Enzyme System (genetics)
• Female
• Genetic Variation
• Genotype
• Glutathione Transferase (genetics)
• Haplotypes
• Humans
• Hydroxyprostaglandin Dehydrogenases (genetics)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Risk Factors
• Urinary Bladder Neoplasms (etiology, genetics)