CYP17 Genetic Variation and Risk of Breast and Prostate Cancer from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3)

  1. Veronica Wendy Setiawan1,
  2. Fredrick R. Schumacher2,3,
  3. Christopher A. Haiman1,
  4. Daniel O. Stram1,
  5. Demetrius Albanes4,
  6. David Altshuler5,
  7. Göran Berglund6,
  8. Julie Buring7,
  9. Eugenia E. Calle10,
  10. Françoise Clavel-Chapelon11,
  11. David G. Cox2,3,
  12. J. Michael Gaziano8,12,
  13. Susan E. Hankinson3,9,
  14. Richard B. Hayes4,
  15. Brian E. Henderson1,
  16. Joel N. Hirschhorn5,
  17. Robert Hoover4,
  18. David J. Hunter2,3,
  19. Rudolf Kaaks13,
  20. Laurence N. Kolonel14,
  21. Peter Kraft2,3,
  22. Jing Ma9,
  23. Loïc Le Marchand14,
  24. Jakob Linseisen13,
  25. Eiliv Lund15,
  26. Carmen Navarro16,
  27. Kim Overvad17,
  28. Domenico Palli18,
  29. Petra H.M. Peeters19,
  30. Malcolm C. Pike1,
  31. Elio Riboli20,
  32. Meir J. Stampfer3,
  33. Michael J. Thun10,
  34. Ruth C. Travis21,
  35. Dimitrios Trichopoulos3,
  36. Meredith Yeager4,
  37. Regina G. Ziegler4,
  38. Heather Spencer Feigelson10 and
  39. Stephen J. Chanock4
  1. 1Department of Preventive Medicine, University of Southern California, Los Angeles, California; 2Program in Molecular and Genetic Epidemiology, 3Department of Epidemiology, Harvard School of Public Health, Boston Massachusettes; 4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland; 5Broad Institute of Harvard and MIT, Cambridge, Massachusetts; 6Department of Clinical Sciences, Malmö University Hospital, Malmö, Sweden; Divisions of 7Preventive Medicine and 8Aging and the 9Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; 10American Cancer Society, Atlanta, Georgia; 11INSERM, Institut Gustave Roussy, Villejuif, France; 12VA Boston Healthcare System, Boston, Massachusetts; 13Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany; 14Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii; 15Institute of Community Medicine, University of Tromsö, Tromsö, Norway; 16Department of Epidemiology, Murcia Health Council, Murcia, and CIBER Epidemiologia y Salud Publica (CIBERESP), Spain; 17Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; 18Molecular and Nutritional Epidemiology Unit, SCPO-Scientific Institute of Tuscany, Florence, Italy; 19Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands; 20Imperial College, London, United Kingdom; and 21Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom
  1. Requests for reprints:
    Veronica Wendy Setiawan, Department of Preventive Medicine, USC/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Room 4425, Los Angeles, CA 90033. Phone: 323-865-0411; Fax: 323-865-0127. E-mail: vsetiawa{at}usc.edu

Abstract

CYP17 encodes cytochrome p450c17α, which mediates activities essential for the production of sex steroids. Common germ line variation in the CYP17 gene has been related to inconsistent results in breast and prostate cancer, with most studies focusing on the nonsynonymous single nucleotide polymorphism (SNP) T27C (rs743572). We comprehensively characterized variation in CYP17 by direct sequencing of exons followed by dense genotyping across the 58 kb region around CYP17 in five racial/ethnic populations. Two blocks of strong linkage disequilibrium were identified and nine haplotype-tagging SNPs, including T27C, were chosen to predict common haplotypes (Rh2 ≥ 0.85). These haplotype-tagging SNPs were genotyped in 8,138 prostate cancer cases and 9,033 controls, and 5,333 breast cancer cases and 7,069 controls from the Breast and Prostate Cancer Cohort Consortium. We observed borderline significant associations with prostate cancer for rs2486758 [TC versus TT, odds ratios (OR), 1.07; 95% confidence intervals (95% CI), 1.00-1.14; CC versus TT, OR, 1.09; 95% CI, 0.95-1.26; P trend = 0.04] and rs6892 (AG versus AA, OR, 1.08; 95% CI, 1.00-1.15; GG versus AA, OR, 1.11; 95% CI, 0.95-1.30; P trend = 0.03). We also observed marginally significant associations with breast cancer for rs4919687 (GA versus GG, OR, 1.04; 95% CI, 0.97-1.12, AA versus GG, OR, 1.17; 95% CI, 1.03-1.34; P trend = 0.03) and rs4919682 (CT versus CC, OR, 1.04; 95% CI, 0.97-1.12; TT versus CC, OR, 1.16; 95% CI, 1.01-1.33; P trend = 0.04). Common variation at CYP17 was not associated with circulating sex steroid hormones in men or postmenopausal women. Our findings do not support the hypothesis that common germ line variation in CYP17 makes a substantial contribution to postmenopausal breast or prostate cancer susceptibility. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2237–46)

Footnotes

  • ↵22 http://www.uscnorris.com/MECgenetics

  • ↵23 http://snp500cancer.nci.nih.gov

  • ↵23 http://genome.ucsc.edu/

  • Grant support: National Cancer Institute cooperative agreements UO1-CA98233, UO1-CA98710, UO1-CA98216, and UO1-CA98758 and by the Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics. National Cancer Institute Career Development Award CA116543 (V.W. Setiawan).

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted August 29, 2007.
    • Received June 27, 2007.
    • Revision received August 13, 2007.
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  1. doi: 10.1158/1055-9965.EPI-07-0589 Cancer Epidemiology, Biomarkers & Prevention November 1, 2007 16, 2237
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