학술논문
Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.
Document Type
Academic Journal
Author
Timofeeva MN; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Kinnersley B; Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.; Farrington SM; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Whiffin N; Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.; Palles C; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.; Svinti V; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Lloyd A; Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.; Gorman M; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.; Ooi LY; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Hosking F; Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.; Barclay E; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.; Zgaga L; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Dobbins S; Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.; Martin L; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.; Theodoratou E; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, United Kingdom.; Broderick P; Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.; Tenesa A; Roslin Institute, University of Edinburgh, Easter Bush, Roslin EH25 9RG, United Kingdom.; Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Smillie C; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Grimes G; Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Hayward C; Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Campbell A; Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Generation Scotland, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Porteous D; Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Generation Scotland, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Deary IJ; University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.; Harris SE; Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.; Northwood EL; Section of Epidemiology &Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, UK.; Barrett JH; Section of Epidemiology &Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, UK.; Smith G; Medical Research Institute, University of Dundee, Dundee, UK.; Wolf R; Medical Research Institute, University of Dundee, Dundee, UK.; Forman D; IARC, Cancer Surveillance Unit, Lyon, France.; Morreau H; Department of Pathology, Leiden University Medical Center, The Netherlands.; Ruano D; Department of Pathology, Leiden University Medical Center, The Netherlands.; Tops C; Department of Clinical Genetics, Leiden University Medical Center, The Netherlands.; Wijnen J; Department of Human Genetics, Leiden University Medical Center, The Netherlands.; Schrumpf M; Department of Pathology, Leiden University Medical Center, The Netherlands.; Boot A; Department of Pathology, Leiden University Medical Center, The Netherlands.; Vasen HF; Department of Gastroenterology, Leiden University Medical Center, The Netherlands.; Hes FJ; Department of Clinical Genetics, Leiden University Medical Center, The Netherlands.; van Wezel T; Department of Pathology, Leiden University Medical Center, The Netherlands.; Franke A; Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.; Lieb W; Institute of Epidemiology, Christian-Albrechts-University Kiel, Kiel.; Schafmayer C; Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.; Hampe J; Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.; Buch S; Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.; Propping P; Institute of Human Genetics, University Hospital Bonn, Bonn, Germany.; Hemminki K; Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.; Center for Primary Health Care Research, Lund University, 205 02 Malmö, Sweden.; Försti A; Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.; Center for Primary Health Care Research, Lund University, 205 02 Malmö, Sweden.; Westers H; University of Groningen, University Medical Centre Groningen, Department of Genetics, PO Box 30001, 9700 RB Groningen, the Netherlands.; Hofstra R; University of Groningen, University Medical Centre Groningen, Department of Genetics, PO Box 30001, 9700 RB Groningen, the Netherlands.; Department of Clinical Genetics, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands.; Pinheiro M; Department of Genetics, Portuguese Oncology Institute and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.; Pinto C; Department of Genetics, Portuguese Oncology Institute and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.; Teixeira M; Department of Genetics, Portuguese Oncology Institute and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.; Ruiz-Ponte C; Fundación Pública Galega de Medicina Xenómica (FPGMX), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clínico, 15706 Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain.; Fernández-Rozadilla C; Fundación Pública Galega de Medicina Xenómica (FPGMX), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clínico, 15706 Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain.; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.; Carracedo A; Fundación Pública Galega de Medicina Xenómica (FPGMX), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clínico, 15706 Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain.; Castells A; Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, 08036 Barcelona, Catalonia, Spain.; Castellví-Bel S; Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, 08036 Barcelona, Catalonia, Spain.; Campbell H; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, United Kingdom.; Bishop DT; Section of Epidemiology &Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, UK.; Tomlinson IP; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.; Dunlop MG; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.; Houlston RS; Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
Subject
Language
English
Abstract
Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10(-7)), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10(-7)); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10(-7) and OR = 1.09, P = 7.4 × 10(-8)); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10(-9)), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 × 10(-6)). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10(-4)) and DNA mismatch repair genes (P = 6.1 × 10(-4)) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.