Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the prostate cancer prevention trial

Douglas K. Price, Cindy H. Chau, Cathee Till, Phyllis J. Goodman, Robin J. Leach, Teresa L. Johnson-Pais, Ann W. Hsing, Ashraful Hoque, Howard L. Parnes, Jeannette M. Schenk, Catherine M. Tangen, Ian M. Thompson, Juergen K.V. Reichardt, William D. Figg

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

BACKGROUND: Prostate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment. METHODS: A nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. RESULTS: There were significant associations of genetic polymorphisms in steroid 5a-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend=.03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend=.01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend <.05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; Ptrend <.05) were significantly associated with both circulating hormone levels and prostate cancer risk. CONCLUSIONS: Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted.

Original languageEnglish (US)
Pages (from-to)2332-2340
Number of pages9
JournalCancer
Volume122
Issue number15
DOIs
StatePublished - Aug 2016

Keywords

  • Androgen
  • Genetics
  • Metabolism
  • Polymorphism
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Price, D. K., Chau, C. H., Till, C., Goodman, P. J., Leach, R. J., Johnson-Pais, T. L., Hsing, A. W., Hoque, A., Parnes, H. L., Schenk, J. M., Tangen, C. M., Thompson, I. M., Reichardt, J. K. V., & Figg, W. D. (2016). Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the prostate cancer prevention trial. Cancer, 122(15), 2332-2340. https://doi.org/10.1002/cncr.30071