ArticleCancer discovery2021
DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.
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Article in Cancer discovery, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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52citing papers in PubMed, 1 pooled it
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.
- ERN GENTURIS guidelines on constitutional mismatch repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management.European journal of human genetics : EJHG · 2024Guideline
- Tumor-derived cell-free DNA detected in cerebrospinal fluid enables minimally invasive profiling of pediatric brain tumors.The Journal of clinical investigation · 2026Trial
- Distinct mutational signature and clonal evolution in constitutional mismatch repair deficiency-associated high-grade gliomas.iScience · 2026Article
- Loss of KDM6A-mediated genomic instability and metabolic reprogramming regulates response to therapeutic perturbations in bladder cancer.Nature communications · 2026Article
- Patterns of hypermutation shape tumorigenesis and immunotherapy response in mismatch-repair-deficient glioma.Nature genetics · 2026Article
- Therapeutic targeting of mismatch repair-deficient cancers.Nature reviews. Clinical oncology · 2025Review
- Microsatellite instability and PD-L1 expression in sarcomas: current evidence and clinical perspectives.Medical oncology (Northwood, London, England) · 2025Review
- Prospective characterization of germline variants in patients with gliomas and glioneuronal tumors.Acta neuropathologica · 2025Article
- Tamoxifen induces PI3K activation in uterine cancer.Nature genetics · 2025Article
- Novel Strategies for Improved Treatment of O6-Methylguanine-DNA Methyltransferase Promoter-Methylated Glioma.Medical research archives · 2025Article
- AlphaMissense for Identifying Pathogenic Missense Mutations in DNA Damage Repair Genes in Cancer.JCO precision oncology · 2025Article
- Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency.Nature communications · 2025Article
- Constitutional Mismatch Repair Deficiency, the Most Aggressive Cancer Predisposition Syndrome : Clinical Presentation, Surveillance, and Management.Journal of Korean Neurosurgical Society · 2025Article
- A redefined InDel taxonomy provides insights into mutational signatures.Nature genetics · 2025Article
- POLE Mutation Associated With Microsatellite Instability and High Tumor Mutational Burden Confers Exquisite Sensitivity to Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer: A Case Report and Genomic Database Analysis.Clinical lung cancer · 2025Article
- Genomic and transcriptomic sequencing in prostate cancer.Current opinion in oncology · 2025Review
- A Potent, Selective, Small-Molecule Inhibitor of DHX9 Abrogates Proliferation of Microsatellite Instable Cancers with Deficient Mismatch Repair.Cancer research · 2025Article
- Review
- Report of the sixth meeting of the European Consortium 'Care for CMMRD' (CFamilial cancer · 2024Article
- Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides.Nature genetics · 2024Article
Corrections and comments
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Authors and funding
55 authors at 20 institutions in 8 countries.
Jiil Chung *Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Yosef E Maruvka *Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts.
Sumedha SudhamanProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Jacalyn KellyProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Nicholas J HaradhvalaMassachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts.
Vanessa BianchiProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Melissa EdwardsProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Victoria J ForsterProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Nuno M NunesProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID 0000-0002-3879-9757
Melissa A GalatiProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Martin KomosaProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Shriya DeshmukhDepartment of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
Vanja CabricDepartment of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
Scott DavidsonProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Matthew ZatzmanProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Nicholas LightProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Reid HayesProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Ledia BrungaProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Nathaniel D AndersonProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID 0000-0003-4523-6327
Ben HoDepartment of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Karl P HodelDepartment of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University of Medicine, New Orleans, Louisiana.
Robert SiddawayThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID 0000-0003-2013-9467
A Sorana MorrissyCumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.ORCID 0000-0001-8526-562X
Daniel C BowersDepartment of Pediatrics and Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.ORCID 0000-0002-3947-2481
Valérie LaroucheDepartment of Pediatrics, Centre Mere-enfant Soleil du CHU de Quebec, CRCHU de Quebec, Universite Laval, Quebec City, Quebec, Canada.ORCID 0000-0002-9773-0995
Annika BronsemaDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Michael OsbornDepartment of Haematology and Oncology, Women's and Children's Hospital, North Adelaide, South Australia, Australia.ORCID 0000-0002-1288-9930
Kristina A ColeDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.ORCID 0000-0003-0064-2882
Enrico OpocherPediatric Oncology and Hematology, Azienda Ospedaliera-Universita' degli Studi di Padova, Padova, Italy.
Gary MasonDepartment of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
Gregory A ThomasDivision of Pediatric Hematology-Oncology, Oregon Health and Science University, Portland, Oregon.
Ben GeorgeDivision of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
David S ZieglerKids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia.
Scott LindhorstNeuro-Oncology, Department of Neurosurgery, and Department of Medicine, Division of Hematology/Medical Oncology, Medical University of South Carolina Charleston, South Carolina.
Magimairajan VananDepartment of Pediatric Hematology-Oncology, Cancer Care Manitoba; Research Institute in Oncology and Hematology (RIOH), University of Manitoba, Winnipeg, Manitoba, Canada.ORCID 0000-0003-2015-0615
Michal Yalon-OrenPediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to the Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
Alyssa T ReddyDivision of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.
Maura MassiminoPediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milano, Italy.ORCID 0000-0002-5506-2001
Patrick TombocDepartment of Pediatrics Section of Hematology-Oncology, WVU Medicine Children's, Morgantown, West Virginia.ORCID 0000-0002-1255-4719
An Van DammeDivision of Hematology and Oncology, Department of Pediatrics, Cliniques Universitaires Saint-Luc, Brussels, Belgium.ORCID 0000-0002-7114-201X
Alexander LossosDepartment of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Carol DurnoZane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
Melyssa AronsonZane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.ORCID 0000-0002-7503-5799
Daniel A MorgensternDepartment of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.ORCID 0000-0002-4859-1108
Eric BouffetDepartment of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID 0000-0002-6832-6539
Annie HuangThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Michael D TaylorThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Anita VillaniDepartment of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
David MalkinDepartment of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Cynthia E HawkinsThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Zachary F PursellDepartment of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University of Medicine, New Orleans, Louisiana.
Adam ShlienProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Thomas A KunkelGenome Integrity Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Durham, North Carolina.
Gad Getz *Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts. uri.tabori@sickkids.ca gadgetz@broadinstitute.org.ORCID 0000-0002-0936-0753
Uri Tabori *Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. uri.tabori@sickkids.ca gadgetz@broadinstitute.org.
Hospital for Sick Children · CAUniversity of Toronto · CABroad Institute · USMount Sinai Hospital · CATulane University · USAzienda Ospedale - Università Padova · ITBrain Tumour Research · GBCancerCare Manitoba · CACenter for Cancer and Blood Disorders · USChildren's Cancer Institute Australia · AUChildren's Hospital of Philadelphia · USChildren's Hospital of Pittsburgh · USCliniques Universitaires Saint-Luc · BEEdmond and Lily Safra Children's Hospital · ILFondazione IRCCS Istituto Nazionale dei Tumori · ITHebrew University of Jerusalem · ILHôtel-Dieu de Québec · CAMcGill University Health Centre · CAMedical College of Wisconsin · USMedical University of South Carolina · US
Funding
West Virginia IDEA-CTRU54GM104942 · NIGMS · WEST VIRGINIA UNIVERSITY · PI Sally Lynn Hodder · 2012 to 2026
$81.0MStudies Of DNA Mismatch RepairZIAES065089 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI KUNKEL, THOMAS A · 2009 to 2025
$17.8MInvestigation of human DNA polymerase epsilon variantsR01ES028271 · NIEHS · TULANE UNIVERSITY OF LOUISIANA · PI Zachary F Pursell · 2017 to 2026
$3.6MCanadian Institutes for Health Research PJT-156006CIHR 108188NIEHS NIH HHS R01 ES028271NIGMS NIH HHS U54 GM104942
Abstract
Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.
Indexed as
Cell Transformation, NeoplasticDNA-Directed DNA PolymeraseDNA Mismatch RepairGene Expression Regulation, NeoplasticMicrosatellite InstabilityExome SequencingHumansNeoplasmsDNA-Directed DNA Polymerase
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