ArticleCell2017
Comprehensive Analysis of Hypermutation in Human Cancer.
Open access · bronzeAbstract read
In one paragraph
Article in Cell, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 477 papers, 2 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
477citing papers in PubMed, 2 pooled it
30.0field-weighted citation impact, top 1% of its field
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
477 citing papers in PubMed, 2 syntheses or guidelines pooled it, 786 citations in OpenAlex.
- Demystifying the potential of lipid-based nanocarriers in targeting brain malignancies.Naunyn-Schmiedeberg's archives of pharmacology · 2024Pooled it
- IDH mutation, glioma immunogenicity, and therapeutic challenge of primary mismatch repair deficient IDH-mutant astrocytoma PMMRDIA: a systematic review.Molecular oncology · 2024Pooled it
- A randomized phase II/III study of paclitaxel/carboplatin/metformin versus paclitaxel/carboplatin/placebo as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: An NRG oncology/GOG study.Gynecologic oncology · 2025Trial
- Temozolomide Followed by Combination With Low-Dose Ipilimumab and Nivolumab in Patients With Microsatellite-Stable, OJournal of clinical oncology : official journal of the American Society of Clinical Oncology · 2022Trial
- Trial
- Deficiency in POLE Exonuclease Causes Synthetic Lethality in Highly Aneuploid Cancer Cells.Cancer research · 2026Article
- Molecular subtyping and POLE mutation spectrum in endometrial carcinoma.The Indian journal of medical research · 2026Article
- Combined inhibition of CDK4/6 and PI3K pathways exhibit highly synergistic activity and translational potential in Ewing sarcoma.Translational oncology · 2026Article
- Cellular and Immunotherapy for Pediatric Brain Tumors: A Primer.Current oncology (Toronto, Ont.) · 2026Review
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- Molecular characterization of mismatch repair deficient tumors in young Jordanian patients.Discover oncology · 2026Article
- 'AnbioRxiv : the preprint server for biology · 2026Article
- Co-Mutation of CREBBP/EP300 and POLE/POLD1 Identifies a TMB-High Subset of MSS CRC.International journal of molecular sciences · 2026Article
- Interpreting the effects of DNA polymerase variants at the structural level.Molecular oncology · 2026Article
- Gallbladder cancer with dual genetic variants of PMS2 and BRCA2: a case report.Clinical journal of gastroenterology · 2026Article
- Dissecting cancer in a non-mammalian model: genomic insights from lemon frost geckos.BMC biology · 2026Article
- Mutation enrichment in targeted panels flags immunotherapy-responsive POLE-driven hypermutated microsatellite-stable colorectal cancers.NPJ precision oncology · 2026Article
- Clinical implications of immune checkpoint inhibitor in chemotherapy-resistant advanced endometrial cancer with a pathogenicInternational cancer conference journal · 2026Article
- Prognostic, Predictive, and Clinical Relevance of DNA Damage Repair Alterations in Biliary Tract Cancers.Cancers · 2026Review
- Unsupervised Deep Representation Learning and Probabilistic Clustering for the Systems-Level Discovery of Germline Mutation Signatures in Pediatric Cancers.Biomedicines · 2026Article
417 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
62 authors at 20 institutions in 9 countries.
Brittany B CampbellProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Nicholas LightProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
David FabrizioFoundation Medicine, Inc., Cambridge, MA, USA.
Matthew ZatzmanProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Fabio FuligniProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Richard de BorjaProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Scott DavidsonProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
Melissa EdwardsProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Julia A ElvinFoundation Medicine, Inc., Cambridge, MA, USA.
Karl P HodelDepartment of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA.
Walter J ZahurancikThe Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
Zucai SuoThe Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
Tatiana LipmanProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Katharina WimmerDivision of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
Christian P KratzPediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
Daniel C BowersDepartment of Pediatrics and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Pauline Allen Gill Center for Cancer and Blood Disorders, Children's Health, Dallas, TX, USA.
Theodore W LaetschDepartment of Pediatrics and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Pauline Allen Gill Center for Cancer and Blood Disorders, Children's Health, Dallas, TX, USA.
Gavin P DunnDepartment of Neurological Surgery, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.
Tanner M JohannsDepartment of Neurological Surgery, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Matthew R GrimmerDivision of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Ivan V SmirnovDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Valérie LaroucheDepartment of Pediatrics, Centre Mère-enfant Soleil du CHU de Québec, CRCHU de Québec, Université Laval, Quebec City, QC, Canada.
David SamuelDepartment of Hematology-Oncology, Valley Children's Hospital, Madera, CA, USA.
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, SA, Australia.
Duncan StearnsDepartment of Pediatrics-Hematology and Oncology, UH Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
Pichai RamanDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Kristina A ColeDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Phillip B StormDivision of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Michal YalonDepartment of Pediatric Hematology-Oncology, Sheba Medical Center, Tel Hashomer, Israel.
Enrico OpocherPediatric Oncology & Hematology, Azienda Ospedaliera-Università degli Studi di Padova, Via Giustiniani n.1, Padova, Italy.
Gary MasonDepartment of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
Gregory A ThomasDivision of Pediatric Hematology-Oncology, Oregon Health & Science University, Portland, OR, USA.
Magnus SabelDepartment of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg & Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
Ben GeorgeDivision of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
David S ZieglerKids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW, Australia.
Scott LindhorstNeuro-Oncology, Department of Neurosurgery, and Department of Medicine, Division of Hematology/Medical Oncology, Medical University of South Carolina, Charleston, SC, USA.
Vanan Magimairajan IssaiDepartment of Pediatric Hematology-Oncology, Cancer Care Manitoba; Research Institute in Oncology and Hematology (RIOH), University of Manitoba, Winnipeg, MB, Canada.
Shlomi ConstantiniDepartment of Pediatric Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
Helen ToledanoDepartment of Pediatric Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
Ronit ElhasidDepartment of Hematology-Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Roula FarahDepartment of Pediatrics, Saint George Hospital University Medical Center, Beirut, Lebanon.
Rina DvirDepartment of Pediatric Hematology/Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Peter DirksDepartment of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
Annie HuangThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Melissa A GalatiProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Jiil ChungProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Vijay RamaswamyDivision of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
Meredith S IrwinDivision of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
Melyssa AronsonZane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada.
Carol DurnoZane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada; Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada.
Michael D TaylorDepartment of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
Gideon RechaviCancer Research Center and Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
John M MarisDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Eric BouffetDivision of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
Cynthia HawkinsThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
Joseph F CostelloDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
M Stephen MeynDepartment of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Center for Human Genomics and Precision Medicine, University of Wisconsin, Madison, WI, USA.
Zachary F PursellDepartment of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA.
David MalkinDivision of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
Uri TaboriProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: uri.tabori@sickkids.ca.
Adam ShlienProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address: adam.shlien@sickkids.ca.
Hospital for Sick Children · CANeurological Surgery · USUniversity of Toronto · CACenter for Cancer and Blood Disorders · USChildren's Hospital of Philadelphia · USFoundation Medicine (United States)Sheba Medical Center · ILTel Aviv Sourasky Medical Center · ILThe Ohio State University · USTulane University · USUniversity of Pennsylvania · USAzienda Ospedaliera di Padova · ITCancerCare Manitoba · CAChildren's Hospital Central California · USChildren's Hospital of Pittsburgh · USInnsbruck Medical University · ATMedical College of Wisconsin · USMedical University of South Carolina · USMedizinische Hochschule Hannover · DEMount Sinai Hospital · CA
Funding
Tissue CoreP50CA097257 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Joseph F Costello · 2002 to 2026
$57.4MProject 4: Multi-modality Metabolic Imaging for Monitoring Molecular Sub-types of GliomaP01CA118816 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Pavithra Viswanath · 2007 to 2026
$44.7MInvestigation of human DNA polymerase epsilon variantsR01ES028271 · NIEHS · TULANE UNIVERSITY OF LOUISIANA · PI Zachary F Pursell · 2017 to 2026
$3.6MRoles of Human DNA Polymearse Epsilon in Mutagenesis and Genome StabilityR00ES016780 · NIEHS · TULANE UNIVERSITY OF LOUISIANA · PI PURSELL, ZACHARY F · 2009 to 2011
$746kMutagenesis, tumorigenesis and human DNA polymerase epsilonR56ES026821 · NIEHS · TULANE UNIVERSITY OF LOUISIANA · PI PURSELL, ZACHARY F · 2016 to 2016
$150kNCI NIH HHS P01 CA118816NCI NIH HHS P50 CA097257NIEHS NIH HHS R00 ES016780NIEHS NIH HHS R01 ES028271NIEHS NIH HHS R56 ES026821
Abstract
We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.
Indexed as
AdultChildCluster AnalysisDNA Polymerase IIDNA Polymerase IIIDNA ReplicationHumansMutationNeoplasmsPoly-ADP-Ribose Binding ProteinsDNA Polymerase IIDNA Polymerase IIIPOLD1 protein, humanPOLE protein, humanPoly-ADP-Ribose Binding Proteinscancer genomicscancer predispositionDNA repairDNA replicationhypermutationimmune checkpoint inhibitorsmismatch repairmutator
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