Meta-Analysis

. 2015 Apr;67(4):649-57.

doi: 10.1016/j.eururo.2014.09.020. Epub 2014 Sep 30.

A genome-wide pleiotropy scan for prostate cancer risk

Orestis A Panagiotou¹, Ruth C Travis², Daniele Campa³, Sonja I Berndt¹, Sara Lindstrom⁴, Peter Kraft⁴, Fredrick R Schumacher⁵, Afshan Siddiq⁶, Stefania I Papatheodorou⁷, Janet L Stanford⁸, Demetrius Albanes¹, Jarmo Virtamo⁹, Stephanie J Weinstein¹, W Ryan Diver¹⁰, Susan M Gapstur¹⁰, Victoria L Stevens¹⁰, Heiner Boeing¹¹, H Bas Bueno-de-Mesquita¹², Aurelio Barricarte Gurrea¹³, Rudolf Kaaks¹⁴, Kay-Tee Khaw¹⁵, Vittorio Krogh¹⁶, Kim Overvad¹⁷, Elio Riboli¹⁸, Dimitrios Trichopoulos¹⁹, Edward Giovannucci²⁰, Meir Stampfer⁴, Christopher Haiman⁵, Brian Henderson⁵, Loic Le Marchand²¹, J Michael Gaziano²², David J Hunter²³, Stella Koutros¹, Meredith Yeager²⁴, Robert N Hoover¹; PRACTICAL Consortium; Stephen J Chanock²⁵, Sholom Wacholder¹, Timothy J Key², Konstantinos K Tsilidis²⁶

Collaborators, Affiliations

Affiliations

¹ Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
² Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA, USA.
⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.
⁷ Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹ Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
¹⁰ Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
¹¹ Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
¹² Department of Epidemiology and Biostatistics, Imperial College School of Public Health, London, UK; Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, Netherlands; Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
¹³ Navarre Public Health Institute, Pamplona, Spain; Consortium for Biomedical Research in Epidemiology and Public Health, Madrid, Spain.
¹⁴ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
¹⁵ Clinical Gerontology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁶ Epidemiology and Prevention Unit, Department of Preventive & Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
¹⁷ Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
¹⁸ Department of Epidemiology and Biostatistics, Imperial College School of Public Health, London, UK.
¹⁹ Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA, USA; Hellenic Health Foundation, Athens, Greece; Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
²⁰ Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA, USA; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
²¹ University of Hawaii Cancer Center, Honolulu, HI, USA.
²² Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Aging, Brigham and Women's Hospital, Boston, MA, USA.
²³ Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA, USA; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
²⁴ Core Genotyping Facility Frederick National Laboratory for Cancer Research, Gaithersburg, MD, USA.
²⁵ Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Core Genotyping Facility Frederick National Laboratory for Cancer Research, Gaithersburg, MD, USA.
²⁶ Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Department of Hygiene and Epidemiology, University of Ioannina, School of Medicine, Ioannina, Greece. Electronic address: kostas.tsilidis@ceu.ox.ac.uk.

PMID: 25277271
PMCID: PMC4359641
DOI: 10.1016/j.eururo.2014.09.020

Meta-Analysis

A genome-wide pleiotropy scan for prostate cancer risk

Orestis A Panagiotou et al. Eur Urol. 2015 Apr.

. 2015 Apr;67(4):649-57.

doi: 10.1016/j.eururo.2014.09.020. Epub 2014 Sep 30.

Authors

Affiliations

¹ Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
² Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA, USA.
⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.
⁷ Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹ Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
¹⁰ Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
¹¹ Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
¹² Department of Epidemiology and Biostatistics, Imperial College School of Public Health, London, UK; Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, Netherlands; Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
¹³ Navarre Public Health Institute, Pamplona, Spain; Consortium for Biomedical Research in Epidemiology and Public Health, Madrid, Spain.
¹⁴ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
¹⁵ Clinical Gerontology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁶ Epidemiology and Prevention Unit, Department of Preventive & Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
¹⁷ Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
¹⁸ Department of Epidemiology and Biostatistics, Imperial College School of Public Health, London, UK.
¹⁹ Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA, USA; Hellenic Health Foundation, Athens, Greece; Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
²⁰ Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA, USA; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
²¹ University of Hawaii Cancer Center, Honolulu, HI, USA.
²² Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Aging, Brigham and Women's Hospital, Boston, MA, USA.
²³ Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA, USA; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
²⁴ Core Genotyping Facility Frederick National Laboratory for Cancer Research, Gaithersburg, MD, USA.
²⁵ Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Core Genotyping Facility Frederick National Laboratory for Cancer Research, Gaithersburg, MD, USA.
²⁶ Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Department of Hygiene and Epidemiology, University of Ioannina, School of Medicine, Ioannina, Greece. Electronic address: kostas.tsilidis@ceu.ox.ac.uk.

PMID: 25277271
PMCID: PMC4359641
DOI: 10.1016/j.eururo.2014.09.020

Abstract

Background: No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS).

Objective: To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer.

Design, setting, and participants: SNPs implicated in any phenotype other than prostate cancer (p≤10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24,534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.

Outcome measurements and statistical analysis: Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated.

Results and limitations: A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p=1.6×10(-6)), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95% CI 1.16-1.27; p=3.22×10(-18)). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86-0.94; p=2.5×10(-6)). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12, 95% CI 1.06-1.19; p=4.67×10(-5)); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL.

Conclusions: We did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in prostate cancer etiology.

Patient summary: We evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified.

Keywords: Aggressive prostate cancer; Genome-wide association study; Glycine; Pleiotropy; Single-nucleotide polymorphism.

PubMed Disclaimer

Conflict of interest statement

Financial disclosures: Konstantinos K. Tsilidis certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Figures

**Figure 1**
Manhattan plot for the 4666 single-nucleotide polymorphisms (SNPs) evaluated in the genome-wide pleiotropy scan. Breast and Prostate Cancer Cohort Consortium (BPC3) results are shown in Light Orange and the meta-analysis results for the three strongest SNPs are shown in orange.

See this image and copyright information in PMC

Comment in

Pleiotropy in aggressive prostate cancer?
Cox A. Cox A. Eur Urol. 2015 Apr;67(4):658-9. doi: 10.1016/j.eururo.2014.11.029. Epub 2014 Nov 24. Eur Urol. 2015. PMID: 25468285 No abstract available.

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A genome-wide pleiotropy scan for prostate cancer risk

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A genome-wide pleiotropy scan for prostate cancer risk

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