ArticleAmerican journal of human genetics2022
Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.
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Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 2 of them syntheses that pooled it.
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48citing papers in PubMed, 2 pooled it
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Who cites it
48 citing papers in PubMed, 2 syntheses or guidelines pooled it, 74 citations in OpenAlex.
- Japanese society for cancer of the colon and rectum (JSCCR) guidelines 2024 for the clinical practice of hereditary colorectal cancer.International journal of clinical oncology · 2026Guideline
- Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision.The British journal of surgery · 2024Guideline
- Gene regulatory mechanisms downstream of DNA methylation.Nature reviews. Genetics · 2026Review
- Integrating germline and tumor sequencing to improve hereditary cancer diagnosis and care.European journal of human genetics : EJHG · 2026Review
- Integration of multi-omics data uncovers novel germline susceptibility candidates in early-onset colorectal cancer.European journal of human genetics : EJHG · 2026Article
- Sequencing approaches in hereditary cancer testing: strengths, limitations and future directions.European journal of human genetics : EJHG · 2026Review
- Motif-centered analyses reveal universal and tissue-specific mutagenic mechanisms operating in the human body.NAR cancer · 2026Article
- Human PMS1-dependent non-canonical mismatch repair engages with MBD4 to repair methylated CpG deamination.Nucleic acids research · 2026Article
- Impact of Multigene Panel Testing in High-Risk Uveal Melanoma Patients.Pigment cell & melanoma research · 2026Article
- Motif-Centered Analyses Reveal Universal and Tissue-Specific Mutagenic Mechanisms Operating in the Human Body.bioRxiv : the preprint server for biology · 2026Article
- Biallelic germline MBD4 mutations predispose to colorectal polyposis, hypermutated AML, and schwannomas.Familial cancer · 2026Article
- Germline haploinsufficiency of MUTYH causes mutational signature SBS18 in multiple tumour types and specifically raises colorectal cancer risk.NPJ precision oncology · 2026Article
- Familial Adenomatous Polyposis-Risk of Cancer, Cancer Prevention, and Long-Term Consequences: Learnings from Five Decades with the Danish Polyposis Register.APMIS : acta pathologica, microbiologica, et immunologica Scandinavica · 2026Review
- Genome Sequencing of Undiagnosed European Patients Suspected of Hereditary Cancer: Diagnostic Yield and Identification of Candidate Causative Variants.JCO precision oncology · 2026Article
- A founder heterozygous mutation in methyl-CpG binding domain protein 4 (MBD4) prevalent among Israeli Christian Arabs predisposes to increased mutagenesis.Haematologica · 2026Article
- Mbd4 and MutSα protect cells from spontaneous deamination of 5-methylcytosine.Nucleic acids research · 2026Article
- Towards a WHO classification of genetic tumour syndromes.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- Genetic Predisposition to Hematologic Malignancies.Cold Spring Harbor perspectives in medicine · 2025Review
- Review
- Inherited Susceptibility to Cancer: Past, Present and Future.Annals of human genetics · 2025Review
Corrections and comments
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Authors and funding
72 authors at 20 institutions in 12 countries.
Claire PallesInstitute of Cancer and Genomic Sciences, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Hannah D WestInstitute of Medical Genetics, Division of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff, UK.
Edward ChewWalter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Sara GalavottiInstitute of Cancer and Genomic Sciences, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Christoffer FlensburgWalter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Judith E GrollemanDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
Erik A M JansenDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
Helen CurleyInstitute of Cancer and Genomic Sciences, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Laura ChegwiddenInstitute of Cancer and Genomic Sciences, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Edward H Arbe-BarnesWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Nicola LanderInstitute of Medical Genetics, Division of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff, UK.
Rebekah TruscottInstitute of Medical Genetics, Division of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff, UK.
Judith PaganMolecular Genetics Laboratory, South East Scotland Genetic Service, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Ashish BajelPeter MacCallum Cancer Center and Royal Melbourne Hospital, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia.
Kitty SherwoodEdinburgh Cancer Research Centre, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XR, UK.
Lynn MartinInstitute of Cancer and Genomic Sciences, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Huw ThomasSt Mark's Hospital, Imperial College London, London, UK.
Demetra GeorgiouGenomic Medicine, Imperial College Healthcare Trust and North West Thames Regional Genetics Service, Northwick Park, Harrow, UK.
Florentia FostiraMolecular Diagnostics Laboratory, NCSR Demokritos, Athens, Greece.
Yael GoldbergRaphael Recanati Genetic Institute, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
David J AdamsWellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Simone A M van der BiezenDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
Michael ChristieWalter 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.
Mark ClendenningColorectal 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.
Laura E ThomasInstitute of Life Sciences, Swansea University, Swansea SA28PP, UK.
Constantinos DeltasCenter of Excellence in Biobanking and Biomedical Research and Molecular Medicine Research Center, University of Cyprus Medical School, Nicosia, Cyprus.
Aleksandar J DimovskiCenter for Biomolecular Pharmaceutical Analyzes, UKIM Faculty of Pharmacy, 1000 Skopje, Republic of Macedonia.
Dagmara DymerskaHereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland.
Jan LubinskiHereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland.
Khalid MahmoodColorectal 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.
Rachel S van der PostDepartment of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
Mathijs SandersDepartment of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Jürgen WeitzDepartment of Surgical Research, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Jenny C TaylorOxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Clare TurnbullInstitute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.
Lilian VreedeDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
Tom van WezelDepartment of Pathology, Leiden University Medical Center, 2300 Leiden, the Netherlands.
Celina WhalleyInstitute of Cancer and Genomic Sciences, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Claudia Arnedo-PacInstitute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain.
Giulio CaravagnaInstitute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.
William CrossCancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
Daniel ChubbInstitute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.
Anna FrangouWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Andreas J GruberManchester Interdisciplinary Biocentre, University of Manchester, Manchester M1 7DN, UK.
Ben KinnersleyInstitute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.
Boris NoyvertInstitute of Cancer and Genomic Sciences, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
David ChurchWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Trevor GrahamBarts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Richard HoulstonInstitute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.
Nuria Lopez-BigasInstitute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain.
Andrea SottorivaCancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
David WedgeManchester Interdisciplinary Biocentre, University of Manchester, Manchester M1 7DN, UK.
Genomics England Research Consortium
CORGI Consortium
WGS500 Consortium
Mark A JenkinsUniversity 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.
Roland P KuiperDepartment 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.
Andrew W RobertsWalter 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.
Jeremy P CheadleInstitute of Medical Genetics, Division of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff, UK.
Marjolijn J L LigtenbergDepartment 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.
Nicoline HoogerbruggeDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
Viktor H KoelzerDepartment of Pathology and Molecular Pathology, University Hospital Zurich, University of Zurich, Zürich, Switzerland.
Andres Dacal RivasServicio de Digestivo, Hospital Lucus Augusti, Instituto de Investigación Sanitaria de Santiago, Lugo, Galicia, Spain.
Ingrid M WinshipGenomic 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.
Clara Ruiz PonteFundación 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.
Daniel D BuchananColorectal 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.
Derek G PowerDepartment of Medical Oncology, Cork University Hospital, Cork, Ireland.
Andrew GreenDepartment of Clinical Genetics, Children's Health Ireland, Dublin, Ireland; School of Medicine University College, Dublin, Ireland.
Ian P M TomlinsonEdinburgh Cancer Research Centre, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XR, UK. Electronic address: ian.tomlinson@igmm.ed.ac.uk.
Julian R SampsonInstitute of Medical Genetics, Division of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff, UK. Electronic address: sampson@cf.ac.uk.
Ian J MajewskiWalter 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.
Richarda M de VoerDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
Radboud University Nijmegen · NLUniversity of Birmingham · GBThe University of Melbourne · AUCardiff University · GBInstitute of Cancer Research · GBCentre for Human Genetics · GBThe Royal Melbourne Hospital · AUEdinburgh Cancer Research · GBInstitute for Research in Biomedicine · ESInternational Hereditary Cancer Center · PLUniversity College London · GBUniversity of Manchester · GBWalter and Eliza Hall Institute of Medical Research · AUCentro de Investigación Biomédica en Red · ESCork University Hospital · IEErasmus MC · NLHospital Universitario Lucus Augusti · ESLeiden University Medical Center · NLNational Centre of Scientific Research "Demokritos" · GRQueen Mary University of London · GB
Funding
Data sharing: the Colon Cancer Family Registry CohortU01CA167551 · NCI · UNIVERSITY OF MELBOURNE · PI Daniel David BUCHANAN, Steven Gallinger · 2018 to 2026
$16.8MCancer Research UK 25514Cancer Research UK 27327Cancer Research UK 27963Department of HealthMedical Research Council MC_PC_16035Medical Research Council MR/V000292/1NCI NIH HHS U01 CA167551
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.
Indexed as
Adenomatous Polyposis ColiColorectal NeoplasmsUveal NeoplasmsEndodeoxyribonucleasesGenetic Predisposition to DiseaseGerm CellsGerm-Line MutationHumansEndodeoxyribonucleasesMBD4 protein, human5′-methylcytosine deaminationcolorectal cancermutational signaturemutator phenotypepolyposis
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