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

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

Author information

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.

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.

PMID:
25642631
DOI:
10.1038/ng.3202
[Indexed for MEDLINE]

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