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Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.
Shlien, Adam; Campbell, Brittany B; de Borja, Richard; Alexandrov, Ludmil B; Merico, Daniele; Wedge, David; Van Loo, Peter; Tarpey, Patrick S; Coupland, Paul; Behjati, Sam; Pollett, Aaron; Lipman, Tatiana; Heidari, Abolfazl; Deshmukh, Shriya; Avitzur, Na'ama; Meier, Bettina; Gerstung, Moritz; Hong, Ye; Merino, Diana M; Ramakrishna, Manasa; Remke, Marc; Arnold, Roland; Panigrahi, Gagan B; Thakkar, Neha P; Hodel, Karl P; Henninger, Erin E; Göksenin, A Yasemin; Bakry, Doua; Charames, George S; Druker, Harriet; Lerner-Ellis, Jordan; Mistry, Matthew; Dvir, Rina; Grant, Ronald; Elhasid, Ronit; Farah, Roula; Taylor, Glenn P; Nathan, Paul C; Alexander, Sarah; Ben-Shachar, Shay; Ling, Simon C; Gallinger, Steven; Constantini, Shlomi; Dirks, Peter; Huang, Annie; Scherer, Stephen W; Grundy, Richard G; Durno, Carol; Aronson, Melyssa; Gartner, Anton.
Afiliação
  • Shlien A; 1] Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ont
  • Campbell BB; 1] Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [3] Institute of Medical Science, Faculty of Medicine, University of Toronto, T
  • de Borja R; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Alexandrov LB; Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
  • Merico D; 1] Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Wedge D; Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
  • Van Loo P; 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK. [2] Department of Human Genetics, University of Leuven, Leuven, Belgium.
  • Tarpey PS; Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
  • Coupland P; Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
  • Behjati S; Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
  • Pollett A; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • Lipman T; 1] Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Heidari A; 1] Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Deshmukh S; 1] Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Avitzur N; 1] Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Meier B; Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
  • Gerstung M; Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
  • Hong Y; Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
  • Merino DM; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Ramakrishna M; Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
  • Remke M; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Arnold R; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Panigrahi GB; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Thakkar NP; 1] Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Hodel KP; Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
  • Henninger EE; Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
  • Göksenin AY; Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
  • Bakry D; 1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
  • Charames GS; 1] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. [2] Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • Druker H; 1] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [2] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Lerner-Ellis J; 1] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. [2] Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. [3] Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Mistry M; 1] Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [3] Institute of Medical Science, Faculty of Medicine, University of Toronto, T
  • Dvir R; Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel-Aviv, Israel.
  • Grant R; 1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
  • Elhasid R; Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel-Aviv, Israel.
  • Farah R; Saint George Hospital University Medical Center, Beirut, Lebanon.
  • Taylor GP; Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Nathan PC; 1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
  • Alexander S; 1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
  • Ben-Shachar S; The Gilbert Israeli Neurofibromatosis Center, Tel Aviv Medical Center, Tel Aviv, Israel.
  • Ling SC; 1] Department of Pediatrics, University of Toronto, Ontario, Canada. [2] Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Gallinger S; 1] The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, Toronto, Ontario, Canada. [2] Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • Constantini S; Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel Aviv Medical Center, Tel Aviv, Israel.
  • Dirks P; 1] The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Huang A; 1] The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [3] Department of Pediatrics, University of Toronto, Ontario, Canada.
  • Scherer SW; 1] Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. [3] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [4] The McLaughli
  • Grundy RG; Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, UK.
  • Durno C; 1] Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, Toronto, Ont
  • Aronson M; The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • Gartner A; Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
Nat Genet ; 47(3): 257-62, 2015 Mar.
Article em En | MEDLINE | ID: mdl-25642631
ABSTRACT
DNA replication-associated mutations are repaired by two components polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Pareamento Incorreto de Bases / Replicação do DNA / Reparo de Erro de Pareamento de DNA Idioma: En Ano de publicação: 2015 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Pareamento Incorreto de Bases / Replicação do DNA / Reparo de Erro de Pareamento de DNA Idioma: En Ano de publicação: 2015 Tipo de documento: Article