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PMID: 25642631 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.

Nature genetics ·Vol. 47 ·No. 3 ·2015-03-00 ·Pages 257-62

Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, Van Loo P, Tarpey PS, Coupland P, Behjati S, Pollett A, Lipman T, Heidari A, Deshmukh S, Avitzur N, Meier B, Gerstung M, Hong Y, Merino DM, Ramakrishna M, Remke M, Arnold R, Panigrahi GB, Thakkar NP, Hodel KP, Henninger EE, Göksenin AY, Bakry D, Charames GS, Druker H, Lerner-Ellis J, Mistry M, Dvir R, Grant R, Elhasid R, Farah R, Taylor GP, Nathan PC, Alexander S, Ben-Shachar S, Ling SC, Gallinger S, Constantini S, Dirks P, Huang A, Scherer SW, Grundy RG, Durno C, Aronson M, Gartner A, Meyn MS, Taylor MD, Pursell ZF, Pearson CE, Malkin D, Futreal PA, Stratton MR, Bouffet E, Hawkins C, Campbell PJ, Tabori U, Biallelic Mismatch Repair Deficiency Consortium

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.

MeSH Terms
Base Pair Mismatch Brain Neoplasms/genetics DNA Mismatch Repair DNA Repair DNA Replication/genetics DNA-Directed DNA Polymerase/genetics Exons Germ-Line Mutation Humans Microsatellite Instability
Chemicals
DNA-Directed DNA Polymerase
Authors & Affiliations
62 authors, click to expand affiliations / ORCID
Shlien Adam
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.
Campbell Brittany B
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.
de Borja Richard
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Alexandrov Ludmil B ORCID
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Merico Daniele
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 David
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Van Loo Peter ORCID
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 Patrick S
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Coupland Paul
Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
Behjati Sam
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Pollett Aaron
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
Lipman Tatiana
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 Abolfazl
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 Shriya
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 Na'ama
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 Bettina
Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
Gerstung Moritz ORCID
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Hong Ye
Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
Merino Diana M
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Ramakrishna Manasa
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Remke Marc
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Arnold Roland
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Panigrahi Gagan B
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Thakkar Neha P
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 Karl P
Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
Henninger Erin E
Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
Göksenin A Yasemin
Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
Bakry Doua
1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
Charames George S
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 Harriet
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 Jordan
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 Matthew
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.
Dvir Rina
Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel-Aviv, Israel.
Grant Ronald
1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
Elhasid Ronit
Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel-Aviv, Israel.
Farah Roula
Saint George Hospital University Medical Center, Beirut, Lebanon.
Taylor Glenn P
Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Nathan Paul C ORCID
1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
Alexander Sarah
1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
Ben-Shachar Shay
The Gilbert Israeli Neurofibromatosis Center, Tel Aviv Medical Center, Tel Aviv, Israel.
Ling Simon C
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 Steven
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 Shlomi
Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel Aviv Medical Center, Tel Aviv, Israel.
Dirks Peter
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 Annie
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 Stephen W
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.
Grundy Richard G
Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, UK.
Durno Carol
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.
Aronson Melyssa
The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, Toronto, Ontario, Canada.
Gartner Anton
Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
Meyn M Stephen
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.
Taylor Michael D
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.
Pursell Zachary F
Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
Pearson Christopher E
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.
Malkin David
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.
Futreal P Andrew
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Stratton Michael R
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Bouffet Eric
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.
Hawkins Cynthia
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.
Campbell Peter J
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK. [2] Department of Haematology, University of Cambridge, Cambridge, UK.
Tabori Uri
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.
Biallelic Mismatch Repair Deficiency Consortium
Investigators
40 investigators, click to expand
Shlien Adam
Campbell Brittany B
de Borja Richard
Pollett Aaron
Lipman Tatiana
Heidari Abolfazl
Deshmukh Shriya
Avitzur Na'ama
Merino Diana M
Arnold Roland
Panigrahi Gagan B
Thakkar Neha P
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
Durno Carol
Aronson Melyssa
Meyn M Stephen
Taylor Michael D
Pearson Christopher E
Malkin David
Bouffet Eric
Hawkins Cynthia
Tabori Uri
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
Published
2015-03-00
Epub
2015-00-02
Pages
257-62
Language
English
Region
United States
NLM ID
9216904
Subset
IM
Grants
CIHR · FRN131596 · Canada
Wellcome Trust · 097945 · United Kingdom
Wellcome Trust · 101126 · United Kingdom
Wellcome Trust · 090944 · United Kingdom
CIHR · MOP123268 · Canada
Corrections
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