A large study of Androgen Receptor germline variants and their relation to sex hormone levels and prostate cancer risk. results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium

Sara Lindström, Jing Ma, David Altshuler, Edward Giovannucci, Elio Riboli, Demetrius Albanes, Naomi E. Allen, Sonja I. Berndt, Heiner Boeing, H. Bas Bueno-de-Mesquita, Stephen J. Chanock, Alison M. Dunning, Heather Spencer Feigelson, J. Michael Gaziano, Christopher A. Haiman, Richard B. Hayes, Brian E. Henderson, David J. Hunter, Rudolf Kaaks, Laurence N. KolonelLoic Le Marchand, Carmen Martínez, Kim Overvad, Afshan Siddiq, Meir Stampfer, Pär Stattin, Daniel O. Stram, Michael J. Thun, Dimitrios Trichopoulos, Rosario Tumino, Jarmo Virtamo, Stephanie J. Weinstein, Meredith Yeager, Peter Kraft, Matthew L. Freedman

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years.Along-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes. Objective and Methods: We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels. Results: We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P=4.73×10-5) and estradiol (P=0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively). Conclusions: This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.

Original languageEnglish (US)
Pages (from-to)E121-E127
JournalJournal of Clinical Endocrinology and Metabolism
Volume95
Issue number9
DOIs
StatePublished - Sep 2010

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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