title: Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.
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.
authors: 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, Ontario, Canada.
authors: Adam
authors: A
authors: Shlien
authors: 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, Toronto, Ontario, Canada.
authors: Brittany B
authors: BB
authors: Campbell
authors: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Richard
authors: R
authors: de Borja
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: Ludmil B
authors: 0000000335964515
authors: LB
authors: Alexandrov
authors: 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.
authors: Daniele
authors: D
authors: Merico
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: David
authors: D
authors: Wedge
authors: 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.
authors: Peter
authors: 0000000302921949
authors: P
authors: Van Loo
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: Patrick S
authors: PS
authors: Tarpey
authors: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors: Paul
authors: P
authors: Coupland
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: Sam
authors: S
authors: Behjati
authors: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors: Aaron
authors: A
authors: Pollett
authors: 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.
authors: Tatiana
authors: T
authors: Lipman
authors: 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.
authors: Abolfazl
authors: A
authors: Heidari
authors: 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.
authors: Shriya
authors: S
authors: Deshmukh
authors: 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.
authors: Na'ama
authors: N
authors: Avitzur
authors: Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
authors: Bettina
authors: B
authors: Meier
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: Moritz
authors: 000000016709963X
authors: M
authors: Gerstung
authors: Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
authors: Ye
authors: Y
authors: Hong
authors: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Diana M
authors: DM
authors: Merino
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: Manasa
authors: M
authors: Ramakrishna
authors: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Marc
authors: M
authors: Remke
authors: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Roland
authors: R
authors: Arnold
authors: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Gagan B
authors: GB
authors: Panigrahi
authors: 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.
authors: Neha P
authors: NP
authors: Thakkar
authors: Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
authors: Karl P
authors: KP
authors: Hodel
authors: Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
authors: Erin E
authors: EE
authors: Henninger
authors: Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
authors: A Yasemin
authors: AY
authors: Göksenin
authors: 1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
authors: Doua
authors: D
authors: Bakry
authors: 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.
authors: George S
authors: GS
authors: Charames
authors: 1] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [2] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Harriet
authors: H
authors: Druker
authors: 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.
authors: Jordan
authors: J
authors: Lerner-Ellis
authors: 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, Toronto, Ontario, Canada.
authors: Matthew
authors: M
authors: Mistry
authors: Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel-Aviv, Israel.
authors: Rina
authors: R
authors: Dvir
authors: 1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
authors: Ronald
authors: R
authors: Grant
authors: Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel-Aviv, Israel.
authors: Ronit
authors: R
authors: Elhasid
authors: Saint George Hospital University Medical Center, Beirut, Lebanon.
authors: Roula
authors: R
authors: Farah
authors: Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: Glenn P
authors: GP
authors: Taylor
authors: 1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
authors: Paul C
authors: 0000000303340871
authors: PC
authors: Nathan
authors: 1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
authors: Sarah
authors: S
authors: Alexander
authors: The Gilbert Israeli Neurofibromatosis Center, Tel Aviv Medical Center, Tel Aviv, Israel.
authors: Shay
authors: S
authors: Ben-Shachar
authors: 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.
authors: Simon C
authors: SC
authors: Ling
authors: 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.
authors: Steven
authors: S
authors: Gallinger
authors: Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel Aviv Medical Center, Tel Aviv, Israel.
authors: Shlomi
authors: S
authors: Constantini
authors: 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.
authors: Peter
authors: P
authors: Dirks
authors: 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.
authors: Annie
authors: A
authors: Huang
authors: 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 McLaughlin Centre, University of Toronto, Toronto, Canada.
authors: Stephen W
authors: SW
authors: Scherer
authors: Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, UK.
authors: Richard G
authors: RG
authors: Grundy
authors: 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, Ontario, Canada.
authors: Carol
authors: C
authors: Durno
authors: The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors: Melyssa
authors: M
authors: Aronson
authors: Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
authors: Anton
authors: A
authors: Gartner
authors: 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. [3] Department of Pediatrics, University of Toronto, Ontario, Canada. [4] Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: M Stephen
authors: MS
authors: Meyn
authors: 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.
authors: Michael D
authors: MD
authors: Taylor
authors: Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
authors: Zachary F
authors: ZF
authors: Pursell
authors: 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.
authors: Christopher E
authors: CE
authors: Pearson
authors: 1] Program in Genetics and Genome Biology, 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.
authors: David
authors: D
authors: Malkin
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: P Andrew
authors: PA
authors: Futreal
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: Michael R
authors: MR
authors: Stratton
authors: 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.
authors: Eric
authors: E
authors: Bouffet
authors: 1] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. [2] The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [3] Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: Cynthia
authors: C
authors: Hawkins
authors: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK. [2] Department of Haematology, University of Cambridge, Cambridge, UK.
authors: Peter J
authors: PJ
authors: Campbell
authors: 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] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [4] Department of Pediatrics, University of Toronto, Ontario, Canada.
authors: Uri
authors: U
authors: Tabori
mesh_terms: D020137:Base Pair Mismatch; D001932:Brain Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair; D004260:DNA Repair; D004261:DNA Replication / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005091:Exons; D018095:Germ-Line Mutation; D006801:Humans; D053842:Microsatellite Instability
chemical_list: D004259:DNA-Directed DNA Polymerase