. 2015 May 5:6:6889.

doi: 10.1038/ncomms7889.

Two susceptibility loci identified for prostate cancer aggressiveness

Sonja I Berndt¹, Zhaoming Wang², Meredith Yeager², Michael C Alavanja¹, Demetrius Albanes¹, Laufey Amundadottir¹, Gerald Andriole³, Laura Beane Freeman¹, Daniele Campa⁴, Geraldine Cancel-Tassin⁵, Federico Canzian⁶, Jean-Nicolas Cornu¹, Olivier Cussenot⁵, W Ryan Diver⁷, Susan M Gapstur⁷, Henrik Grönberg⁸, Christopher A Haiman⁹, Brian Henderson⁹, Amy Hutchinson¹⁰, David J Hunter¹¹, Timothy J Key¹², Suzanne Kolb¹³, Stella Koutros¹, Peter Kraft¹¹, Loic Le Marchand¹⁴, Sara Lindström¹¹, Mitchell J Machiela¹, Elaine A Ostrander¹⁵, Elio Riboli¹⁶, Fred Schumacher⁹, Afshan Siddiq¹⁷, Janet L Stanford¹⁸, Victoria L Stevens⁷, Ruth C Travis¹², Konstantinos K Tsilidis¹⁹, Jarmo Virtamo²⁰, Stephanie Weinstein¹, Fredrik Wilkund⁸, Jianfeng Xu²¹, S Lilly Zheng²¹, Kai Yu¹, William Wheeler²², Han Zhang¹; African Ancestry Prostate Cancer GWAS Consortium; Joshua Sampson¹, Amanda Black¹, Kevin Jacobs¹, Robert N Hoover¹, Margaret Tucker¹, Stephen J Chanock¹

Collaborators, Affiliations

Collaborators

African Ancestry Prostate Cancer GWAS Consortium:
Sue A Ingles⁹, Rick A Kittles²³, Sara S Strom²⁴, Benjamin A Rybicki²⁵, Barbara Nemesure²⁶, William B Isaacs²⁷, Wei Zheng²⁸, Curtis A Pettaway²⁹, Edward D Yeboah³⁰, Yao Tettey³⁰, Richard B Biritwum³⁰, Andrew A Adjei³⁰, Evelyn Tay³⁰, Ann Truelove³¹, Shelley Niwa³¹, Anand P Chokkalingam³², Esther M John³³, Adam B Murphy³⁴, Lisa B Signorello³⁵, John Carpten³⁶, M Cristina Leske²⁶, Suh-Yuh Wu²⁶, Anslem J M Hennis³⁷, Christine Neslund-Dudas²⁵, Ann W Hsing³³, Lisa Chu³³, Phyllis J Goodman³⁸, Eric A Klein³⁹, John S Witte⁴⁰, Graham Casey⁹, Sam Kaggwa⁴¹, Michael B Cook¹, Daniel O Stram⁹, William J Blot⁴²

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
² 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA [2] Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, USA.
³ Division of Urologic Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA.
⁴ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁵ CeRePP, Assistance Publique-Hôpitaux de Paris, UPMC University Paris 6, Paris, France.
⁶ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁷ Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA.
⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm 17177, Sweden.
⁹ Department of Preventative Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
¹⁰ Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, USA.
¹¹ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
¹² Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN, UK.
¹³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
¹⁴ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
¹⁵ National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
¹⁶ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London SW7 2AZ, UK.
¹⁷ Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK.
¹⁸ 1] Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA [2] Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington 98195, USA.
¹⁹ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece.
²⁰ Department of Chronic Disease Prevention, National Institute for Health and Welfare, FI-00271 Helsinki, Finland.
²¹ Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
²² Information Management Services Inc., Rockville, Maryland 20852, USA.
²³ University of Arizona College of Medicine and University of Arizona Cancer Center, Tucson, AZ, USA.
²⁴ Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
²⁵ Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
²⁶ Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
²⁷ James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, MD, USA.
²⁸ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
²⁹ Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
³⁰ 1] Korle Bu Teaching Hospital, Accra, Ghana. [2] University of Ghana Medical School, Accra, Ghana.
³¹ Westat, Rockville, MD, USA.
³² School of Public Health, University of California, Berkeley, CA, USA.
³³ 1] Cancer Prevention Institute of California, Fremont, CA, USA. [2] Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, CA, USA.
³⁴ Department of Urology, Northwestern University, Chicago, IL, USA.
³⁵ 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA [2] International Epidemiology Institute, Rockville, MD, USA.
³⁶ The Translational Genomics Research Institute, Phoenix, AZ, USA.
³⁷ 1] Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA. [2] Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados.
³⁸ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³⁹ Glickman Urological &Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.
⁴⁰ 1] Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. [2] Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
⁴¹ Department of Surgery, Makerere University College of Health Sciences, Kampala, Uganda.
⁴² 1] Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA. [2] International Epidemiology Institute, Rockville, MD, USA.

PMID: 25939597
PMCID: PMC4422072
DOI: 10.1038/ncomms7889

Two susceptibility loci identified for prostate cancer aggressiveness

Sonja I Berndt et al. Nat Commun. 2015.

. 2015 May 5:6:6889.

doi: 10.1038/ncomms7889.

Authors

Collaborators

African Ancestry Prostate Cancer GWAS Consortium:
Sue A Ingles⁹, Rick A Kittles²³, Sara S Strom²⁴, Benjamin A Rybicki²⁵, Barbara Nemesure²⁶, William B Isaacs²⁷, Wei Zheng²⁸, Curtis A Pettaway²⁹, Edward D Yeboah³⁰, Yao Tettey³⁰, Richard B Biritwum³⁰, Andrew A Adjei³⁰, Evelyn Tay³⁰, Ann Truelove³¹, Shelley Niwa³¹, Anand P Chokkalingam³², Esther M John³³, Adam B Murphy³⁴, Lisa B Signorello³⁵, John Carpten³⁶, M Cristina Leske²⁶, Suh-Yuh Wu²⁶, Anslem J M Hennis³⁷, Christine Neslund-Dudas²⁵, Ann W Hsing³³, Lisa Chu³³, Phyllis J Goodman³⁸, Eric A Klein³⁹, John S Witte⁴⁰, Graham Casey⁹, Sam Kaggwa⁴¹, Michael B Cook¹, Daniel O Stram⁹, William J Blot⁴²

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
² 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA [2] Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, USA.
³ Division of Urologic Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA.
⁴ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁵ CeRePP, Assistance Publique-Hôpitaux de Paris, UPMC University Paris 6, Paris, France.
⁶ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁷ Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA.
⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm 17177, Sweden.
⁹ Department of Preventative Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
¹⁰ Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, USA.
¹¹ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
¹² Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN, UK.
¹³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
¹⁴ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
¹⁵ National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
¹⁶ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London SW7 2AZ, UK.
¹⁷ Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK.
¹⁸ 1] Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA [2] Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington 98195, USA.
¹⁹ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece.
²⁰ Department of Chronic Disease Prevention, National Institute for Health and Welfare, FI-00271 Helsinki, Finland.
²¹ Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
²² Information Management Services Inc., Rockville, Maryland 20852, USA.
²³ University of Arizona College of Medicine and University of Arizona Cancer Center, Tucson, AZ, USA.
²⁴ Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
²⁵ Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
²⁶ Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
²⁷ James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, MD, USA.
²⁸ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
²⁹ Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
³⁰ 1] Korle Bu Teaching Hospital, Accra, Ghana. [2] University of Ghana Medical School, Accra, Ghana.
³¹ Westat, Rockville, MD, USA.
³² School of Public Health, University of California, Berkeley, CA, USA.
³³ 1] Cancer Prevention Institute of California, Fremont, CA, USA. [2] Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, CA, USA.
³⁴ Department of Urology, Northwestern University, Chicago, IL, USA.
³⁵ 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA [2] International Epidemiology Institute, Rockville, MD, USA.
³⁶ The Translational Genomics Research Institute, Phoenix, AZ, USA.
³⁷ 1] Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA. [2] Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados.
³⁸ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³⁹ Glickman Urological &Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.
⁴⁰ 1] Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. [2] Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
⁴¹ Department of Surgery, Makerere University College of Health Sciences, Kampala, Uganda.
⁴² 1] Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA. [2] International Epidemiology Institute, Rockville, MD, USA.

PMID: 25939597
PMCID: PMC4422072
DOI: 10.1038/ncomms7889

Abstract

Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

There are no conflicts of interest.

Figures

**Figure 1**
Regional association plots of the two novel loci associated with Gleason score as a quantitative trait among cases: (a) chromosome 5q14.3 (rs35148638) and (b) chromosome 3q26.31 (rs78943174). Shown are the −log₁₀ association p-values from the linear regression model for the 4,545 cases in stage 1 (dots and lower purple diamond) and −log₁₀ p-values from the linear regression model for the 12,518 cases in the combined stage 1-3 analysis (upper diamond).

See this image and copyright information in PMC

References

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29. - PubMed
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Two susceptibility loci identified for prostate cancer aggressiveness

Collaborators

Affiliations

Two susceptibility loci identified for prostate cancer aggressiveness

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous