Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes.
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.
Figueroa
Jonine D
JD
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, MD, USA. figueroaj@mail.nih.gov
Malats
Núria
N
García-Closas
Montserrat
M
Real
Francisco X
FX
Silverman
Debra
D
Kogevinas
Manolis
M
Chanock
Stephen
S
Welch
Robert
R
Dosemeci
Mustafa
M
Lan
Qing
Q
Tardón
Adonina
A
Serra
Consol
C
Carrato
Alfredo
A
García-Closas
Reina
R
Castaño-Vinyals
Gemma
G
Rothman
Nathaniel
N
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001189:Aryl Hydrocarbon Hydroxylases; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D001749:Urinary Bladder Neoplasms / Q000209:etiology / Q000235:genetics*
D015096:3-Hydroxysteroid Dehydrogenases; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001189:Aryl Hydrocarbon Hydroxylases; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D006911:Hydroxyprostaglandin Dehydrogenases; C497396:ARNT protein, human; C487341:AKR1C3 protein, human; C585496:CYP1B1 protein, human