Bladder cancer risk and genetic variation in AKR1C3 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, Nathaniel Rothman

Research output: Contribution to journalArticle

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 (∼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.

Original languageEnglish (US)
Pages (from-to)1955-1962
Number of pages8
JournalCarcinogenesis
Volume29
Issue number10
DOIs
StatePublished - 2008
Externally publishedYes

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Urinary Bladder Neoplasms
Single Nucleotide Polymorphism
Genes
Aryl Hydrocarbon Receptor Nuclear Translocator
Cytochrome P-450 CYP1A1
Polycyclic Aromatic Hydrocarbons
Homozygote
Carcinogens
Amines
Odds Ratio
Genotype
Confidence Intervals
Cytochrome P-450 CYP3A
Aryl Hydrocarbon Receptors
Cytochrome P-450 CYP1A2
Heterozygote
Smoke
Non-Hodgkin's Lymphoma
Haplotypes
Walking

ASJC Scopus subject areas

  • Cancer Research

Cite this

Figueroa, J. D., Malats, N., García-Closas, M., Real, F. X., Silverman, D., Kogevinas, M., ... Rothman, N. (2008). Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes. Carcinogenesis, 29(10), 1955-1962. https://doi.org/10.1093/carcin/bgn163

Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes. / Figueroa, Jonine D.; Malats, Núria; García-Closas, Montserrat; Real, Francisco X.; Silverman, Debra; Kogevinas, Manolis; Chanock, Stephen; Welch, Robert; Dosemeci, Mustafa; Lan, Qing; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Castaño-Vinyals, Gemma; Rothman, Nathaniel.

In: Carcinogenesis, Vol. 29, No. 10, 2008, p. 1955-1962.

Research output: Contribution to journalArticle

Figueroa, JD, Malats, N, García-Closas, M, Real, FX, Silverman, D, Kogevinas, M, Chanock, S, Welch, R, Dosemeci, M, Lan, Q, Tardón, A, Serra, C, Carrato, A, García-Closas, R, Castaño-Vinyals, G & Rothman, N 2008, 'Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes', Carcinogenesis, vol. 29, no. 10, pp. 1955-1962. https://doi.org/10.1093/carcin/bgn163
Figueroa JD, Malats N, García-Closas M, Real FX, Silverman D, Kogevinas M et al. Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes. Carcinogenesis. 2008;29(10):1955-1962. https://doi.org/10.1093/carcin/bgn163
Figueroa, Jonine D. ; Malats, Núria ; García-Closas, Montserrat ; Real, Francisco X. ; Silverman, Debra ; Kogevinas, Manolis ; Chanock, Stephen ; Welch, Robert ; Dosemeci, Mustafa ; Lan, Qing ; Tardón, Adonina ; Serra, Consol ; Carrato, Alfredo ; García-Closas, Reina ; Castaño-Vinyals, Gemma ; Rothman, Nathaniel. / Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes. In: Carcinogenesis. 2008 ; Vol. 29, No. 10. pp. 1955-1962.
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AU - Real, Francisco X.

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AU - Lan, Qing

AU - Tardón, Adonina

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N2 - 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.

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