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

Adam Shlien; Brittany B Campbell; Richard de Borja; Ludmil B Alexandrov; Daniele Merico; David Wedge; Peter Van Loo; Patrick S Tarpey; Paul Coupland; Sam Behjati; Aaron Pollett; Tatiana Lipman; Abolfazl Heidari; Shriya Deshmukh; Na'ama Avitzur; Bettina Meier; Moritz Gerstung; Ye Hong; Diana M Merino; Manasa Ramakrishna; Marc Remke; Roland Arnold; Gagan B Panigrahi; Neha P Thakkar; Karl P Hodel; Erin E Henninger; A Yasemin Göksenin; Doua Bakry; George S Charames; Harriet Druker; Jordan Lerner-Ellis; Matthew Mistry; Rina Dvir; Ronald Grant; Ronit Elhasid; Roula Farah; Glenn P Taylor; Paul C Nathan; Sarah Alexander; Shay Ben-Shachar; Simon C Ling; Steven Gallinger; Shlomi Constantini; Peter Dirks; Annie Huang; Stephen W Scherer; Richard G Grundy; Carol Durno; Melyssa Aronson; Anton Gartner; M Stephen Meyn; Michael D Taylor; Zachary F Pursell; Christopher E Pearson; David Malkin; P Andrew Futreal; Michael R Stratton; Eric Bouffet; Cynthia Hawkins; Peter J Campbell; Uri Tabori; Biallelic Mismatch Repair Deficiency Consortium

doi:10.1038/ng.3202

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

Nat Genet. 2015 Mar;47(3):257-62. doi: 10.1038/ng.3202. Epub 2015 Feb 2.

Authors

Adam Shlien¹, Brittany B Campbell², Richard de Borja³, Ludmil B Alexandrov⁴, Daniele Merico⁵, David Wedge⁴, Peter Van Loo⁶, Patrick S Tarpey⁴, Paul Coupland⁷, Sam Behjati⁴, Aaron Pollett⁸, Tatiana Lipman⁹, Abolfazl Heidari⁹, Shriya Deshmukh⁹, Na'ama Avitzur⁹, Bettina Meier¹⁰, Moritz Gerstung⁴, Ye Hong¹⁰, Diana M Merino³, Manasa Ramakrishna⁴, Marc Remke¹¹, Roland Arnold³, Gagan B Panigrahi³, Neha P Thakkar¹², Karl P Hodel¹³, Erin E Henninger¹³, A Yasemin Göksenin¹³, Doua Bakry¹⁴, George S Charames¹⁵, Harriet Druker¹⁶, Jordan Lerner-Ellis¹⁷, Matthew Mistry², Rina Dvir¹⁸, Ronald Grant¹⁴, Ronit Elhasid¹⁸, Roula Farah¹⁹, Glenn P Taylor²⁰, Paul C Nathan¹⁴, Sarah Alexander¹⁴, Shay Ben-Shachar²¹, Simon C Ling²², Steven Gallinger²³, Shlomi Constantini²⁴, Peter Dirks²⁵, Annie Huang²⁶, Stephen W Scherer²⁷, Richard G Grundy²⁸, Carol Durno²⁹, Melyssa Aronson³⁰, Anton Gartner¹⁰, M Stephen Meyn³¹, Michael D Taylor²⁵, Zachary F Pursell¹³, Christopher E Pearson¹², David Malkin³², P Andrew Futreal⁴, Michael R Stratton⁴, Eric Bouffet²⁶, Cynthia Hawkins³³, Peter J Campbell³⁴, Uri Tabori³⁵; Biallelic Mismatch Repair Deficiency Consortium

Collaborators

Biallelic Mismatch Repair Deficiency Consortium:
Adam Shlien, Brittany B Campbell, Richard de Borja, Aaron Pollett, Tatiana Lipman, Abolfazl Heidari, Shriya Deshmukh, Na'ama Avitzur, Diana M Merino, Roland Arnold, Gagan B Panigrahi, Neha P Thakkar, Doua Bakry, George S Charames, Harriet Druker, Jordan Lerner-Ellis, Matthew Mistry, Rina Dvir, Ronald Grant, Ronit Elhasid, Roula Farah, Glenn P Taylor, Paul C Nathan, Sarah Alexander, Shay Ben-Shachar, Simon C Ling, Steven Gallinger, Shlomi Constantini, Peter Dirks, Annie Huang, Stephen W Scherer, Carol Durno, Melyssa Aronson, M Stephen Meyn, Michael D Taylor, Christopher E Pearson, David Malkin, Eric Bouffet, Cynthia Hawkins, Uri Tabori

Affiliations

¹ 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.
² 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.
³ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
⁵ 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.
⁶ 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.
⁷ Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
⁸ Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
⁹ 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.
¹⁰ Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
¹¹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹² 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.
¹³ Department of Biochemistry &Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.
¹⁴ 1] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Ontario, Canada.
¹⁵ 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.
¹⁶ 1] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [2] Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁷ 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.
¹⁸ Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel-Aviv, Israel.
¹⁹ Saint George Hospital University Medical Center, Beirut, Lebanon.
²⁰ Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
²¹ The Gilbert Israeli Neurofibromatosis Center, Tel Aviv Medical Center, Tel Aviv, Israel.
²² 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.
²³ 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.
²⁴ Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel Aviv Medical Center, Tel Aviv, Israel.
²⁵ 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.
²⁶ 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.
²⁷ 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.
²⁸ Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, UK.
²⁹ 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.
³⁰ The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, Toronto, Ontario, Canada.
³¹ 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.
³² 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.
³³ 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.
³⁴ 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK. [2] Department of Haematology, University of Cambridge, Cambridge, UK.
³⁵ 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.

PMID: 25642631
DOI: 10.1038/ng.3202

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.

Publication types

Research Support, Non-U.S. Gov't

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

Substances

DNA-Directed DNA Polymerase

Abstract

Publication types

MeSH terms

Substances

Grants and funding