Christopher Wills1, Yazhou He2, Matthew G Summers1, Yi Lin3, Amanda I Phipps3, Katie Watts1, Philip J Law4, Nada A Al-Tassan5, Timothy S Maughan6, Richard Kaplan7, Richard S Houlston4, Ulrike Peters3, Polly A Newcomb3, Andrew T Chan8, Daniel D Buchanan9, Steve Gallinger10, Loic L Marchand11, Rish K Pai12, Qian Shi13, Steven R Alberts14, Victoria Gray1, Hannah D West1, Valentina Escott-Price15, Malcolm G Dunlop16, Jeremy P Cheadle17. 1. Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. 2. Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK; Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610000, China. 3. Epidemiology Department, University of Washington, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 4. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK. 5. Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia. 6. CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK. 7. MRC Clinical Trials Unit, University College of London, 125 Kingsway, London, WC2B 6NH, UK. 8. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 9. Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia; Centre for Cancer Research, Victorian Comprehensive Cancer Centre, The University of Melbourne, Parkville, Victoria, Australia; Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia. 10. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 11. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA. 12. Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA. 13. Department of Quantitative Science, Mayo Clinic, Rochester, MN, USA. 14. Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA. 15. Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK. 16. Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. 17. Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. Electronic address: cheadlejp@cardiff.ac.uk.
Abstract
BACKGROUND: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome. PATIENTS AND METHODS: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10-5), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas. RESULTS: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10-7). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10-2) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10-8). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10-2). CONCLUSIONS: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.
BACKGROUND: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome. PATIENTS AND METHODS: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10-5), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas. RESULTS: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10-7). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10-2) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10-8). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10-2). CONCLUSIONS: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.
Authors: M Ashburner; C A Ball; J A Blake; D Botstein; H Butler; J M Cherry; A P Davis; K Dolinski; S S Dwight; J T Eppig; M A Harris; D P Hill; L Issel-Tarver; A Kasarskis; S Lewis; J C Matese; J E Richardson; M Ringwald; G M Rubin; G Sherlock Journal: Nat Genet Date: 2000-05 Impact factor: 38.330
Authors: Shaun Purcell; Benjamin Neale; Kathe Todd-Brown; Lori Thomas; Manuel A R Ferreira; David Bender; Julian Maller; Pamela Sklar; Paul I W de Bakker; Mark J Daly; Pak C Sham Journal: Am J Hum Genet Date: 2007-07-25 Impact factor: 11.025
Authors: Emma Dotor; Miriam Cuatrecases; María Martínez-Iniesta; Matilde Navarro; Felip Vilardell; Elisabeth Guinó; Laura Pareja; Agnés Figueras; David G Molleví; Teresa Serrano; Javier de Oca; Miguel A Peinado; Víctor Moreno; Josep Ramón Germà; Gabriel Capellá; Alberto Villanueva Journal: J Clin Oncol Date: 2006-04-01 Impact factor: 44.544
Authors: Anna Abulí; Juan José Lozano; María Rodríguez-Soler; Rodrigo Jover; Xavier Bessa; Jenifer Muñoz; Clara Esteban-Jurado; Ceres Fernández-Rozadilla; Angel Carracedo; Clara Ruiz-Ponte; Joaquín Cubiella; Francesc Balaguer; Luis Bujanda; Josep M Reñé; Juan Clofent; Juan Diego Morillas; David Nicolás-Pérez; Rosa M Xicola; Xavier Llor; Josep M Piqué; Montserrat Andreu; Antoni Castells; Sergi Castellví-Bel Journal: Carcinogenesis Date: 2013-05-27 Impact factor: 4.944
Authors: Axel Walther; Elaine Johnstone; Charles Swanton; Rachel Midgley; Ian Tomlinson; David Kerr Journal: Nat Rev Cancer Date: 2009-06-18 Impact factor: 60.716
Authors: Adam Auton; Lisa D Brooks; Richard M Durbin; Erik P Garrison; Hyun Min Kang; Jan O Korbel; Jonathan L Marchini; Shane McCarthy; Gil A McVean; Gonçalo R Abecasis Journal: Nature Date: 2015-10-01 Impact factor: 49.962
Authors: Yazhou He; Evropi Theodoratou; Xue Li; Farhat V N Din; Peter Vaughan-Shaw; Victoria Svinti; Susan M Farrington; Harry Campbell; Malcolm G Dunlop; Maria Timofeeva Journal: Int J Cancer Date: 2019-07-27 Impact factor: 7.396
Authors: Harpreet Wasan; Angela M Meade; Richard Adams; Richard Wilson; Cheryl Pugh; David Fisher; Benjamin Sydes; Ayman Madi; Bruce Sizer; Charles Lowdell; Gary Middleton; Rachel Butler; Richard Kaplan; Tim Maughan Journal: Lancet Oncol Date: 2014-04-03 Impact factor: 41.316