2. Academic Validation
  3. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

  • Am J Hum Genet. 2022 May 5;109(5):953-960. doi: 10.1016/j.ajhg.2022.03.018.
Claire Palles 1,  Hannah D West 2,  Edward Chew 3,  Sara Galavotti 1,  Christoffer Flensburg 3,  Judith E Grolleman 4,  Erik A M Jansen 4,  Helen Curley 1,  Laura Chegwidden 1,  Edward H Arbe-Barnes 5,  Nicola Lander 2,  Rebekah Truscott 2,  Judith Pagan 6,  Ashish Bajel 7,  Kitty Sherwood 8,  Lynn Martin 1,  Huw Thomas 9,  Demetra Georgiou 10,  Florentia Fostira 11,  Yael Goldberg 12,  David J Adams 13,  Simone A M van der Biezen 4,  Michael Christie 14,  Mark Clendenning 15,  Laura E Thomas 16,  Constantinos Deltas 17,  Aleksandar J Dimovski 18,  Dagmara Dymerska 19,  Jan Lubinski 19,  Khalid Mahmood 15,  Rachel S van der Post 20,  Mathijs Sanders 21,  Jürgen Weitz 22,  Jenny C Taylor 23,  Clare Turnbull 24,  Lilian Vreede 4,  Tom van Wezel 25,  Celina Whalley 1,  Claudia Arnedo-Pac 26,  Giulio Caravagna 24,  William Cross 27,  Daniel Chubb 24,  Anna Frangou 5,  Andreas J Gruber 28,  Ben Kinnersley 24,  Boris Noyvert 1,  David Church 5,  Trevor Graham 29,  Richard Houlston 24,  Nuria Lopez-Bigas 26,  Andrea Sottoriva 27,  David Wedge 28,  Genomics England Research Consortium,  CORGI Consortium,  WGS500 Consortium,  Mark A Jenkins 30,  Roland P Kuiper 31,  Andrew W Roberts 32,  Jeremy P Cheadle 2,  Marjolijn J L Ligtenberg 33,  Nicoline Hoogerbrugge 4,  Viktor H Koelzer 34,  Andres Dacal Rivas 35,  Ingrid M Winship 36,  Clara Ruiz Ponte 37,  Daniel D Buchanan 38,  Derek G Power 39,  Andrew Green 40,  Ian P M Tomlinson 41,  Julian R Sampson 42,  Ian J Majewski 43,  Richarda M de Voer 4
Affiliations

Affiliations

  • 1 Institute of Cancer and Genomic Sciences, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
  • 2 Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff, UK.
  • 3 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • 4 Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
  • 5 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • 6 Molecular Genetics Laboratory, South East Scotland Genetic Service, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
  • 7 Peter MacCallum Cancer Center and Royal Melbourne Hospital, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia.
  • 8 Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XR, UK.
  • 9 St Mark's Hospital, Imperial College London, London, UK.
  • 10 Genomic Medicine, Imperial College Healthcare Trust and North West Thames Regional Genetics Service, Northwick Park, Harrow, UK.
  • 11 Molecular Diagnostics Laboratory, NCSR Demokritos, Athens, Greece.
  • 12 Raphael Recanati Genetic Institute, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 13 Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • 14 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia.
  • 15 Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia.
  • 16 Institute of Life Sciences, Swansea University, Swansea SA28PP, UK.
  • 17 Center of Excellence in Biobanking and Biomedical Research and Molecular Medicine Research Center, University of Cyprus Medical School, Nicosia, Cyprus.
  • 18 Center for Biomolecular Pharmaceutical Analyzes, UKIM Faculty of Pharmacy, 1000 Skopje, Republic of Macedonia.
  • 19 Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland.
  • 20 Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
  • 21 Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 22 Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • 23 Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • 24 Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.
  • 25 Department of Pathology, Leiden University Medical Center, 2300 Leiden, the Netherlands.
  • 26 Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 27 Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
  • 28 Manchester Interdisciplinary Biocentre, University of Manchester, Manchester M1 7DN, UK.
  • 29 Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • 30 University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.
  • 31 Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands; Princess Máxima Center for Pediatric Oncology, 3584 Utrecht, the Netherlands.
  • 32 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Molecular Genetics Laboratory, South East Scotland Genetic Service, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia; University of Melbourne, Department of Medical Biology, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • 33 Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands; Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
  • 34 Department of Pathology and Molecular Pathology, University Hospital Zurich, University of Zurich, Zürich, Switzerland.
  • 35 Servicio de Digestivo, Hospital Lucus Augusti, Instituto de Investigación Sanitaria de Santiago, Lugo, Galicia, Spain.
  • 36 Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Medicine, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
  • 37 Fundación Pública Galega de Medicina Xenómica SERGAS, Grupo de Medicina Xenómica-USC, Instituto de Investigación Sanitaria de Santiago, Centro de Investigación Biomédica en Red de Enfermedades Raras, Santiago de Compostela, Galicia, Spain.
  • 38 Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Melbourne, VIC, Australia.
  • 39 Department of Medical Oncology, Cork University Hospital, Cork, Ireland.
  • 40 Department of Clinical Genetics, Children's Health Ireland, Dublin, Ireland; School of Medicine University College, Dublin, Ireland.
  • 41 Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XR, UK. Electronic address: ian.tomlinson@igmm.ed.ac.uk.
  • 42 Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff, UK. Electronic address: sampson@cf.ac.uk.
  • 43 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.
PMID: 35460607 DOI: 10.1016/j.ajhg.2022.03.018
Abstract

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Keywords

5′-methylcytosine deamination; colorectal cancer; mutational signature; mutator phenotype; polyposis.

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