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CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium

Travis, Ruth C.; Schumacher, Fredrick; Hirschhorn, Joel N.; Kraft, Peter; Allen, Naomi E.; Albanes, Demetrius; Berglund, Göran LU ; Berndt, Sonja I.; Boeing, Heiner and Bueno-de-Mesquita, H. Bas, et al. (2009) In Cancer Epidemiology Biomarkers & Prevention 18(10). p.2734-2744
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... (More)
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 nuclecitide polymorphisms (htSNP) that efficiently predict common variants in U.S. and Europe-an 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. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2734-44) (Less)
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Cancer Epidemiology Biomarkers & Prevention
volume
18
issue
10
pages
2734 - 2744
publisher
American Association for Cancer Research
external identifiers
  • wos:000270702100023
  • scopus:70350114283
ISSN
1538-7755
DOI
10.1158/1055-9965.EPI-09-0496
language
English
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yes
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dc1d90a0-f312-4651-96cc-da581ee4ea37 (old id 1507511)
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2009-11-20 13:37:18
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2017-11-19 03:44:17
@article{dc1d90a0-f312-4651-96cc-da581ee4ea37,
  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 nuclecitide polymorphisms (htSNP) that efficiently predict common variants in U.S. and Europe-an 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. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2734-44)},
  author       = {Travis, Ruth C. and Schumacher, Fredrick and Hirschhorn, Joel N. and Kraft, Peter and Allen, Naomi E. and Albanes, Demetrius and Berglund, Göran and Berndt, Sonja I. and Boeing, Heiner and Bueno-de-Mesquita, H. Bas and Calle, Eugenia E. and Chanock, Stephen and Dunning, Alison M. and Hayes, Richard and Feigelson, Heather Spencer and Gaziano, J. Michael and Giovannucci, Edward and Haiman, Christopher A. and Henderson, Brian E. and Kaaks, Rudolf and Kolonel, Laurence N. and Ma, Jing and Rodriguez, Laudina and Riboli, Elio and Stampfer, Meir and Stram, Daniel O. and Thun, Michael J. and Tjonneland, Anne and Trichopoulos, Dimitrios and Vineis, Paolo and Virtamo, Jarmo and Le Marchand, Loic and Hunter, David J.},
  issn         = {1538-7755},
  language     = {eng},
  number       = {10},
  pages        = {2734--2744},
  publisher    = {American Association for Cancer Research},
  series       = {Cancer Epidemiology Biomarkers & Prevention},
  title        = {CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium},
  url          = {http://dx.doi.org/10.1158/1055-9965.EPI-09-0496},
  volume       = {18},
  year         = {2009},
}