HGG Advances (Jul 2021)
Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals
- Hongjie Chen,
- Arunabha Majumdar,
- Lu Wang,
- Siddhartha Kar,
- Kevin M. Brown,
- Helian Feng,
- Constance Turman,
- Joe Dennis,
- Douglas Easton,
- Kyriaki Michailidou,
- Jacques Simard,
- Timothy Bishop,
- Iona C. Cheng,
- Jeroen R. Huyghe,
- Stephanie L. Schmit,
- Tracy A. O’Mara,
- Amanda B. Spurdle,
- Puya Gharahkhani,
- Johannes Schumacher,
- Janusz Jankowski,
- Ines Gockel,
- Melissa L. Bondy,
- Richard S. Houlston,
- Robert B. Jenkins,
- Beatrice Melin,
- Corina Lesseur,
- Andy R. Ness,
- Brenda Diergaarde,
- Andrew F. Olshan,
- Christopher I. Amos,
- David C. Christiani,
- Maria T. Landi,
- James D. McKay,
- Myriam Brossard,
- Mark M. Iles,
- Matthew H. Law,
- Stuart MacGregor,
- Jonathan Beesley,
- Michelle R. Jones,
- Jonathan Tyrer,
- Stacey J. Winham,
- Alison P. Klein,
- Gloria Petersen,
- Donghui Li,
- Brian M. Wolpin,
- Rosalind A. Eeles,
- Christopher A. Haiman,
- Zsofia Kote-Jarai,
- Fredrick R. Schumacher,
- Paul Brennan,
- Stephen J. Chanock,
- Valerie Gaborieau,
- Mark P. Purdue,
- Paul Pharoah,
- Rayjean J. Hung,
- Laufey T. Amundadottir,
- Peter Kraft,
- Bogdan Pasaniuc,
- Sara Lindström
Affiliations
- Hongjie Chen
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- Arunabha Majumdar
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Mathematics, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
- Lu Wang
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
- Siddhartha Kar
- Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Kevin M. Brown
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Helian Feng
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Constance Turman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Joe Dennis
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Douglas Easton
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Kyriaki Michailidou
- Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; Cyprus School of Molecular Medicine, Nicosia, Cyprus
- Jacques Simard
- Department of Molecular Medicine, Faculty of Medicine, Université Laval and Centre de recherche du CHU de Québec-Université Laval, Québec, QC, Canada
- Timothy Bishop
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
- Iona C. Cheng
- Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA
- Jeroen R. Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Stephanie L. Schmit
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Tracy A. O’Mara
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Amanda B. Spurdle
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Puya Gharahkhani
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Johannes Schumacher
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
- Janusz Jankowski
- College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE; Comprehensive Clinical Trials Unit, University College London, London, UK
- Ines Gockel
- Department of Visceral, Transplant, Thoracic, and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
- Melissa L. Bondy
- Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA, USA
- Richard S. Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
- Robert B. Jenkins
- Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA
- Beatrice Melin
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
- Corina Lesseur
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA; International Agency for Research on Cancer, World Health Organization, Lyon, France
- Andy R. Ness
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK; Bristol Dental School, University of Bristol, Bristol, UK
- Brenda Diergaarde
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Andrew F. Olshan
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
- Christopher I. Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
- David C. Christiani
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Maria T. Landi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- James D. McKay
- International Agency for Research on Cancer, World Health Organization, Lyon, France
- Myriam Brossard
- Genetic Epidemiology and Functional Genomics of Multifactorial Diseases Team, Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS-1124, Université Paris Descartes, Paris, France; Prosserman Centre for Population Health Research, Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON, Canada
- Mark M. Iles
- Leeds Institute for Data Analytics, University of Leeds, Leeds, UK
- Matthew H. Law
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia
- Stuart MacGregor
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Jonathan Beesley
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Michelle R. Jones
- Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Jonathan Tyrer
- Department of Oncology, University of Cambridge, Cambridge, UK
- Stacey J. Winham
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
- Alison P. Klein
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Gloria Petersen
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
- Donghui Li
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Brian M. Wolpin
- Department of Medical Oncology, Dana Farber Harvard Cancer Center, Boston, MA, USA
- Rosalind A. Eeles
- Oncogenetics Team, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK
- Christopher A. Haiman
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
- Zsofia Kote-Jarai
- Oncogenetics Team, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK
- Fredrick R. Schumacher
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA; Seidman Cancer Center, University Hospitals, Cleveland, OH, USA
- Paul Brennan
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK
- Stephen J. Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Valerie Gaborieau
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK
- Mark P. Purdue
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Paul Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Rayjean J. Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON, Canada
- Laufey T. Amundadottir
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Peter Kraft
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Bogdan Pasaniuc
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Sara Lindström
- Department of Epidemiology, University of Washington, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Corresponding author
- Journal volume & issue
-
Vol. 2,
no. 3
p. 100041
Abstract
Summary: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
