Abstract
Genes involved in the testosterone biosynthetic pathway – such as CYP17A1, CYP3A4, and SRD5A2 – represent strong candidates for affecting prostate cancer. Previous work has detected associations between individual variants in these three genes and prostate cancer risk and aggressiveness. To more comprehensively evaluate CYP17A1, CYP3A4, and SRD5A2, we undertook a two-phase study of the relationship between their genotypes/haplotypes and prostate cancer. Phase I of the study first searched for single-nucleotide polymorphisms (SNPs) in these genes by resequencing 24 individuals from the Coriell Polymorphism Discovery Resource, 92–110 men from prostate cancer case–control sibships, and by leveraging public databases. In all, 87 SNPs were discovered and genotyped in 276 men from case–control sibships. Those SNPs exhibiting preliminary case–control allele frequency differences, or distinguishing (ie, ‘tagging’) common haplotypes across the genes, were identified for further study (24 SNPs in total). In Phase II of the study, the 24 SNPs were genotyped in an additional 841 men from case–control sibships. Finally, associations between genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2 and prostate cancer were evaluated in the total case–control sample of 1117 brothers from 506 sibships. Family-based analyses detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 SNPs (P-values between 0.006 and 0.05), a CYP3A4 haplotype (P-values 0.05 and 0.009 in nonstratified and stratified analysis, respectively), and two SRD5A2 SNPs in strong linkage disequilibrium (P=0.02). Undertaking a two-phase study comprising SNP discovery, haplotype tagging, and association analyses allowed us to more fully decipher the relation between CYP17A1, CYP3A4, and SRD5A2 and prostate cancer.
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Acknowledgements
This study was supported by Amersham plc., and grants from the National Institutes of Health (CA88164, CA94186) and US Department of Defense (DAMD17-98-1-8589). Part of JSW's work reported in this paper was undertaken during the tenure of a Visiting Scientist Award by the International Agency for Research on Cancer. A number of talented individuals from Aeomica (a research initiative of Amersham plc.) helped with this project. We thank Thuymy Phan, Baoha Nguyen, Steven Song, Tan Tran, Karen Tran, David Jenkins, Daniel Lee, Kevin Holden, Sarita Balabhadra, Jennifer Dam, Danielle Hern, Rachel Stogner, Gail Jackman, and Mark Lewis. Wensheng Chen, Yonggang Ji, Robert T Loder Jr, Jorgen Jonsson, Anders Brinne, and Bonnie Thiel greatly helped with informatic aspects of the project. Finally, we thank Sasha Lazetic, Richard Belcinski, Audrey Shuster, Marek Minarik, and David Shen.
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Loukola, A., Chadha, M., Penn, S. et al. Comprehensive evaluation of the association between prostate cancer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2. Eur J Hum Genet 12, 321–332 (2004). https://doi.org/10.1038/sj.ejhg.5201101
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DOI: https://doi.org/10.1038/sj.ejhg.5201101
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