Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: results from the Prostate Cancer Prevention Trial

Price, Douglas K., Chau, Cindy H., Till, Cathee, Goodman, Phyllis J., Leach, Robin J., Johnson-Pais, Teresa L., Hsing, Ann W., Hoque, Ashraful, Parnes, Howard L., Schenk, Jeannette M., Tangen, Catherine M., Thompson, Ian M., Reichardt, Juergen K. V., and Figg, William 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). pp. 2332-2340.

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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 5-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; P-trend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; P-trend = .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; P-trend < .05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; P-trend < .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.

Item ID: 45511
Item Type: Article (Research - C1)
ISSN: 1097-0142
Keywords: androgen, genetics, metabolism, polymorphism, prostate cancer
Funders: National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research, Cancer Therapy and Research Center (CTRC)
Projects and Grants: NIH Intramural Research Program, NCI Biology of the Prostate Cancer Prevention Trial P01 CA108964, CTRC Support Grant P30 CA054174, NCI Public Health Service Grant CA37429, NCI Public Health Service Grant CA182883
Date Deposited: 24 Aug 2016 10:50
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1112 Oncology and Carcinogenesis > 111299 Oncology and Carcinogenesis not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920102 Cancer and Related Disorders @ 100%
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