Skip to Main Content

An official website of the United States government

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

About this Publication
Title
Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.
Pubmed ID
33058866 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Gastroenterology. 2020 Oct 12
Authors
Guo X, Lin W, Wen W, Huyghe J, Bien S, Cai Q, Harrison T, Chen Z, Qu C, Bao J, Long J, Yuan Y, Wang F, Bai M, Abecasis GR, Albanes D, Berndt SI, Bézieau S, Bishop DT, Brenner H, ...show more Buch S, Burnett-Hartman A, Campbell PT, Castellví-Bel S, Chan AT, Chang-Claude J, Chanock SJ, Cho SH, Conti DV, Chapelle A, Feskens EJM, Gallinger SJ, Giles GG, Goodman PJ, Gsur A, Guinter M, Gunter MJ, Hampe J, Hampel H, Hayes RB, Hoffmeister M, Kampman E, Kang HM, Keku TO, Kim HR, Le Marchand L, Lee SC, Li CI, Li L, Lindblom A, Lindor N, Milne RL, Moreno V, Murphy N, Newcomb PA, Nickerson DA, Offit K, Pearlman R, Pharoah PDP, Platz EA, Potter JD, Rennert G, Sakoda LC, Schafmayer C, Schmit SL, Schoen RE, Schumacher FR, Slattery ML, Su YR, Tangen CM, Ulrich CM, van Duijnhoven FJB, Van Guelpen B, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Wang X, White E, Wolk A, Woods MO, Casey G, Hsu L, Jenkins MA, Gruber SB, Peters U, Zheng W
Affiliations
  • Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address: xingyi.guo@vumc.org.
  • The Kidney Disease Center, the First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Service de Génétique Médicale, Centre Hospitalier Universitaire, Nantes, France.
  • Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany.
  • Department of Medicine I, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany.
...show more
  • Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
  • 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.
  • Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg, Hamburg, Germany.
  • Department of Hematology-Oncology, Chonnam National University Hospital, Hwasun, South Korea.
  • Department of Preventive Medicine and University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
  • Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
  • Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, the Netherlands.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
  • Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
  • Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
  • Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina.
  • Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea.
  • University of Hawaii Cancer Center, Honolulu, Hawaii.
  • National University Cancer Institute, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
  • Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Health Sciences Research, Mayo Clinic, Scottsdale, Arizona.
  • Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; CIBER Epidemiología y Salud Pública, Madrid, Spain.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Public Health, University of Washington, Seattle, Washington.
  • Department of Genome Sciences, University of Washington, Seattle, Washington.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
  • Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Research, Kaiser Permanente Northern California, Oakland, California.
  • Department of General Surgery, University Hospital Rostock, Rostock, Germany.
  • Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
  • Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio.
  • Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
  • Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Memorial University of Newfoundland, Discipline of Genetics, St John's, Newfoundland and Labrador, Canada.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
Abstract

BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.

METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.

RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.

CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

Related CDAS Studies
Related CDAS Projects