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Associations of prostate cancer risk variants with disease aggressiveness: results of the NCI-SPORE Genetics Working Group analysis of 18,343 cases

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Abstract

Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer (PC). It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score (Gleason ≤6, 7, ≥8) and aggressiveness (non-aggressive, intermediate, and aggressive disease). Statistical analyses were used to compare the frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 (G) was significantly and inversely associated with aggressive (OR = 0.77; 95 % CI 0.69–0.87) and high-grade disease (OR = 0.77; 95 % CI 0.68–0.86) in European men. Similar associations with aggressive (OR = 0.72; 95 % CI 0.58–0.89) and high-grade disease (OR = 0.69; 95 % CI 0.54–0.87) were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels (<4.0 ng/mL) in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness.

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Authors and Affiliations

  1. Department of Surgery, Division of Urology, John and Carol Walter Center for Urological Health, NorthShore University Health System, Evanston, IL, USA

    Brian T. Helfand

  2. Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Kimberly A. Roehl, Phillip R. Cooper, Barry B. McGuire & William J. Catalona

  3. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, 3004, Australia

    Liesel M. Fitzgerald

  4. CeRePP ICPCG Group, Hopital Tenon, Assistance Publique-Hopitaux de Paris, 75020, Paris, France

    Geraldine Cancel-Tassin, Jean-Nicolas Cornu & Olivier Cussenot

  5. Genome Analysis Core Facility, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    Scott Bauer, Erin L. Van Blarigan, June M. Chan & John Witte

  6. Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA

    Xin Chen & Dan Mercola

  7. Integrated Cancer Genomics Division, TGen, Phoenix, AZ, USA

    David Duggan

  8. Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA

    Elaine A. Ostrander

  9. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Mary Gwo-Shu

  10. Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, USA

    Zuo-Feng Zhang, Shen-Chih Chang & Somee Jeong

  11. School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Elizabeth T. H. Fontham

  12. Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA

    Gary Smith & James L. Mohler

  13. Division of Cancer Epidemiology and Genetics, Occupational and Environmental Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA

    Sonja I. Berndt

  14. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    Shannon K. McDonnell & Daniel J. Schaid

  15. Department of Surgery, Division of Urology, University of Arizona, Tucson, AZ, USA

    Rick Kittles

  16. Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA

    Benjamin A. Rybicki

  17. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Matthew Freedman & Philip W. Kantoff

  18. Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Mark Pomerantz

  19. Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Joan P. Breyer & Jeffrey R. Smith

  20. Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Timothy R. Rebbeck

  21. Department of Urology, Johns Hopkins University, Baltimore, MD, USA

    William B. Isaacs

  22. University of Umeå ICPCG Group, Umeå, Sweden

    Fredrick Wiklund

  23. Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Stephen N. Thibodeau

  24. Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

    Lisa Cannon-Albright

  25. Department of Urology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    Kathleen A. Cooney

  26. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA

    Stephen J. Chanock

  27. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Janet L. Stanford

  28. Program for Personalized Cancer Care and Department of Surgery, NorthShore University Health System, Evanston, IL, USA

    Jianfeng Xu

  29. Gillings School of Global Public Health Department of Epidemiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jeannette T. Bensen

  30. Epidemiology Branch and Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, USA

    Jack A. Taylor

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  1. Brian T. Helfand
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  2. Kimberly A. Roehl
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  3. Phillip R. Cooper
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  38. Stephen J. Chanock
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  39. Janet L. Stanford
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  40. June M. Chan
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  41. John Witte
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  42. Jianfeng Xu
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  43. Jeannette T. Bensen
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  44. Jack A. Taylor
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  45. William J. Catalona
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Corresponding author

Correspondence to William J. Catalona.

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Helfand, B.T., Roehl, K.A., Cooper, P.R. et al. Associations of prostate cancer risk variants with disease aggressiveness: results of the NCI-SPORE Genetics Working Group analysis of 18,343 cases. Hum Genet 134, 439–450 (2015). https://doi.org/10.1007/s00439-015-1534-9

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