Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.
- Department of Epidemiology, University of Washington, Seattle, WA, USA.
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
- Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- 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.
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
- Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
- Department of Molecular Medicine, Faculty of Medicine, Université Laval and Centre de recherche du CHU de Québec-Université Laval, Québec, QC, Canada.
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
- Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA.
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
- College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE.
- Department of Visceral, Transplant, Thoracic, and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
- Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA, USA.
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
- Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- 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.
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
- International Agency for Research on Cancer, World Health Organization, Lyon, France.
- 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.
- Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
- Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Department of Oncology, University of Cambridge, Cambridge, UK.
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Medical Oncology, Dana Farber Harvard Cancer Center, Boston, MA, USA.
- Oncogenetics Team, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON, Canada.
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.
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