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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.

About this Publication
Title
Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.
Pubmed ID
36539618 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Nat Genet. 2023 Jan; Volume 55 (Issue 1): Pages 89-99
Authors
Fernandez-Rozadilla C , Timofeeva M , Chen Z , Law P , Thomas M , Schmit S , Díez-Obrero V , Hsu L , Fernandez-Tajes J , Palles C , Sherwood K , Briggs S , Svinti V , Donnelly K , Farrington S , Blackmur J , Vaughan-Shaw P , Shu XO , Long J , Cai Q , ...show more Guo X , Lu Y , Broderick P , Studd J , Huyghe J , Harrison T , Conti D , Dampier C , Devall M , Schumacher F , Melas M , Rennert G , Obón-Santacana M , Martín-Sánchez V , Moratalla-Navarro F , Oh JH , Kim J , Jee SH , Jung KJ , Kweon SS , Shin MH , Shin A , Ahn YO , Kim DH , Oze I , Wen W , Matsuo K , Matsuda K , Tanikawa C , Ren Z , Gao YT , Jia WH , Hopper J , Jenkins M , Win AK , Pai R , Figueiredo J , Haile R , Gallinger S , Woods M , Newcomb P , Duggan D , Cheadle J , Kaplan R , Maughan T , Kerr R , Kerr D , Kirac I , Böhm J , Mecklin LP , Jousilahti P , Knekt P , Aaltonen L , Rissanen H , Pukkala E , Eriksson J , Cajuso T , Hänninen U , Kondelin J , Palin K , Tanskanen T , Renkonen-Sinisalo L , Zanke B , Männistö S , Albanes D , Weinstein S , Ruiz-Narvaez E , Palmer J , Buchanan D , Platz E , Visvanathan K , Ulrich C , Siegel E , Brezina S , Gsur A , Campbell P , Chang-Claude J , Hoffmeister M , Brenner H , Slattery M , Potter J , Tsilidis K , Schulze M , Gunter M , Murphy N , Castells A , Castellví-Bel S , Moreira L , Arndt V , Shcherbina A , Stern M , Pardamean B , Bishop T , Giles G , Southey M , Idos G , McDonnell K , Abu-Ful Z , Greenson J , Shulman K , Lejbkowicz F , Offit K , Su YR , Steinfelder R , Keku T , van Guelpen B , Hudson T , Hampel H , Pearlman R , Berndt S , Hayes R , Martinez ME , Thomas S , Corley D , Pharoah P , Larsson S , Yen Y , Lenz HJ , White E , Li L , Doheny K , Pugh E , Shelford T , Chan A , Cruz-Correa M , Lindblom A , Hunter D , Joshi A , Schafmayer C , Scacheri P , Kundaje A , Nickerson D , Schoen R , Hampe J , Stadler Z , Vodicka P , Vodickova L , Vymetalkova V , Papadopoulos N , Edlund C , Gauderman W , Thomas D , Shibata D , Toland A , Markowitz S , Kim A , Chanock S , van Duijnhoven F , Feskens E , Sakoda L , Gago-Dominguez M , Wolk A , Naccarati A , Pardini B , FitzGerald L , Lee SC , Ogino S , Bien S , Kooperberg C , Li C , Lin Y , Prentice R , Qu C , Bézieau S , Tangen C , Mardis E , Yamaji T , Sawada N , Iwasaki M , Haiman C , Le Marchand L , Wu A , Qu C , McNeil C , Coetzee G , Hayward C , Deary I , Harris S , Theodoratou E , Reid S , Walker M , Ooi LY , Moreno V , Casey G , Gruber S , Tomlinson I , Zheng W , Dunlop M , Houlston R , Peters U
Affiliations
  • Edinburgh Cancer Research Centre, Institute of Genomics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute, Barcelona, Spain.
  • Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • Department of Public Health, Richard Doll Building, University of Oxford, Oxford, UK.
  • Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
...show more
  • Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
  • Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
  • The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
  • Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
  • Consortium for Biomedical Research in Epidemiology and Public Health, Madrid, Madrid, Spain.
  • Center for Colorectal Cancer, National Cancer Center Hospital, National Cancer Center, Gyeonggi-do, South Korea.
  • Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi-do, South Korea.
  • Department of Epidemiology and Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea.
  • Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea.
  • Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
  • Department of Social and Preventive Medicine, Hallym University College of Medicine, Okcheon-dong, South Korea.
  • Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
  • Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan.
  • Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
  • Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • School of Public Health, Sun Yat-sen University, Guangzhou, China.
  • State Key Laboratory of Oncogenes and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
  • Division of Oncology, Department of Medicine, Cedars-Sinai Cancer Research Center for Health Equity, Los Angeles, CA, USA.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Division of Biomedical Sciences, Memorial University of Newfoundland, St. John, Ontario, Canada.
  • City of Hope National Medical Center, Translational Genomics Research Institute, Phoenix, AZ, USA.
  • Institute of Medical Genetics, Cardiff University, Cardiff, UK.
  • MRC Clinical Trials Unit, Medical Research Council, Cardiff, UK.
  • MRC Institute for Radiation Oncology, University of Oxford, Oxford, UK.
  • Department of Oncology, University of Oxford, Oxford, UK.
  • Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Department of Surgical Oncology, University Hospital for Tumors, Sestre milosrdnice University Hospital Center, Zagreb, Croatia.
  • Department of Pathology, Central Finland Health Care District, Jyväskylä, Finland.
  • Central Finland Health Care District, Jyväskylä, Finland.
  • Department of Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
  • Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
  • Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
  • Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.
  • Folkhälsan Research Centre, University of Helsinki, Helsinki, Finland.
  • Department of Surgery, Abdominal Centre, Helsinki University Hospital, Helsinki, Finland.
  • Department of Oncology, University of Toronto, Toronto, Ontario, Canada.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
  • Slone Epidemiology Center at Boston University, Boston, MA, USA.
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia.
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
  • Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
  • Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
  • Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
  • Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
  • Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
  • Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
  • Department of Genetics, Stanford University, Stanford, CA, USA.
  • Department of Population and Public Health Sciences, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
  • Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
  • Department of Medical Oncology and Center For Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.
  • Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
  • Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Division of Human Genetics, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
  • Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA.
  • Population Sciences, Disparities and Community Engagement, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.
  • Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Taipei Medical University, Taipei, Taiwan.
  • Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
  • Center for Inherited Disease Research, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Comprehensive Cancer Center, University of Puerto Rico, San Juan, Puerto Rico.
  • Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
  • Department of General Surgery, University Hospital Rostock, Rostock, Germany.
  • Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
  • Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Department of Medicine I, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany.
  • Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
  • Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
  • Department of Oncology Ludwig Center at the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA.
  • Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
  • Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH, USA.
  • Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands.
  • Division of Human Nutrition, Wageningen University and Research, Wageningen, The Netherlands.
  • Genomic Medicine Group, Galician Public Foundation of Genomic Medicine, Servicio Galego de Saude, Santiago de Compostela, Spain.
  • Italian Institute for Genomic Medicine, Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy.
  • National University Cancer Institute, Singapore, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes, France.
  • SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Department of Pediatrics, Nationwide Children's Hospital, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Columbus, OH, USA.
  • Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan.
  • Division of Cohort Research, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan.
  • Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA.
  • Cancer Center, University of Hawaii, Honolulu, HI, USA.
  • Preventative Medicine, University of Southern California, Los Angeles, CA, USA.
  • USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Van Andel Research Institute, Grand Rapids, MI, USA.
  • MRC Human Genetics Unit, Institute of Genomics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
  • Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.
  • Edinburgh Cancer Research Centre, Institute of Genomics and Cancer, University of Edinburgh, Edinburgh, UK. Ian.Tomlinson@ed.ac.uk.
  • Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA. wei.zheng@vanderbilt.edu.
  • Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. malcolm.dunlop@ed.ac.uk.
  • Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK. Richard.Houlston@icr.ac.uk.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. upeters@fredhutch.org.
Abstract

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

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