CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium.

Abstract

Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNP) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 x 10(-5)], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer.

• Authors: Ruth C Travis, Fredrick Schumacher, Joel N Hirschhorn, Peter Kraft, Naomi E Allen, Demetrius Albanes, Goran Berglund, Sonja I Berndt, Heiner Boeing, H Bas Bueno-de-Mesquita, Eugenia E Calle, Stephen Chanock, Alison M Dunning, Richard Hayes, Heather Spencer Feigelson, J Michael Gaziano, Edward Giovannucci, Christopher A Haiman, Brian E Henderson, Rudolf Kaaks, Laurence N Kolonel, Jing Ma, Laudina Rodriguez, Elio Riboli, Meir Stampfer, Daniel O Stram, Michael J Thun, Anne Tjønneland, Dimitrios Trichopoulos, Paolo Vineis, Jarmo Virtamo, Loïc Le Marchand, David J Hunter
• Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (Cancer Epidemiol Biomarkers Prev) Vol. 18 Issue 10 Pg. 2734-44 (Oct 2009) ISSN: 1538-7755 [Electronic] United States
• PMID: 19789370 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Gonadal Steroid Hormones
• Aromatase

Topics

• Aged
• Aromatase (genetics)
• Case-Control Studies
• Cohort Studies
• Disease Progression
• Female
• Genetic Predisposition to Disease
• Genetic Variation
• Gonadal Steroid Hormones (blood, genetics)
• Humans
• Male
• Neoplasm Staging
• Polymorphism, Single Nucleotide
• Prognosis
• Prospective Studies
• Prostatic Neoplasms (blood, enzymology, genetics)
• Risk Factors