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

Nature Genetics volume 47, pages 257262 (2015) | Download Citation



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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U.T. received funding from BRAINchild Canada and the Canadian Institute of Health Research (operating grant MOP123268). C.E.P. received funding from the Canadian Institute of Health Research (operating grant FRN131596). P.J.C. and A.G. are personally funded through Wellcome Trust Senior Clinical and Basic Research Fellowships and are members of the Wellcome-funded COMSIG consortium. S.B. is funded through a Wellcome Trust Research Training Fellowship for Clinicians. B.B.C., M.M. and R.A. are supported by a SickKids Restracomp award. We acknowledge J. Costello for his contribution to the manuscript.

Author information

Author notes

    • Brittany B Campbell
    •  & Richard de Borja

    These authors contributed equally to this work.


  1. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Adam Shlien
    • , Brittany B Campbell
    • , Richard de Borja
    • , Daniele Merico
    • , Tatiana Lipman
    • , Abolfazl Heidari
    • , Shriya Deshmukh
    • , Na'ama Avitzur
    • , Diana M Merino
    • , Roland Arnold
    • , Gagan B Panigrahi
    • , Neha P Thakkar
    • , Matthew Mistry
    • , Stephen W Scherer
    • , M Stephen Meyn
    • , Christopher E Pearson
    • , David Malkin
    •  & Uri Tabori
  2. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Adam Shlien
  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

    • Adam Shlien
    • , George S Charames
    • , Jordan Lerner-Ellis
    •  & Cynthia Hawkins
  4. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Brittany B Campbell
    • , Tatiana Lipman
    • , Abolfazl Heidari
    • , Shriya Deshmukh
    • , Na'ama Avitzur
    • , Marc Remke
    • , Matthew Mistry
    • , Peter Dirks
    • , Annie Huang
    • , Michael D Taylor
    • , Eric Bouffet
    • , Cynthia Hawkins
    •  & Uri Tabori
  5. Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Brittany B Campbell
    •  & Matthew Mistry
  6. Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.

    • Ludmil B Alexandrov
    • , David Wedge
    • , Peter Van Loo
    • , Patrick S Tarpey
    • , Sam Behjati
    • , Moritz Gerstung
    • , Manasa Ramakrishna
    • , P Andrew Futreal
    • , Michael R Stratton
    •  & Peter J Campbell
  7. The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Daniele Merico
    •  & Stephen W Scherer
  8. Department of Human Genetics, University of Leuven, Leuven, Belgium.

    • Peter Van Loo
  9. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.

    • Paul Coupland
  10. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Aaron Pollett
    • , George S Charames
    •  & Jordan Lerner-Ellis
  11. Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.

    • Bettina Meier
    • , Ye Hong
    •  & Anton Gartner
  12. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

    • Neha P Thakkar
    • , Harriet Druker
    • , Stephen W Scherer
    • , M Stephen Meyn
    •  & Christopher E Pearson
  13. Department of Biochemistry & Molecular Biology, Tulane Cancer Center, Tulane University, School of Medicine, New Orleans, Louisiana, USA.

    • Karl P Hodel
    • , Erin E Henninger
    • , A Yasemin Göksenin
    •  & Zachary F Pursell
  14. Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Doua Bakry
    • , Harriet Druker
    • , Ronald Grant
    • , Paul C Nathan
    • , Sarah Alexander
    • , Annie Huang
    • , David Malkin
    • , Eric Bouffet
    •  & Uri Tabori
  15. Department of Pediatrics, University of Toronto, Ontario, Canada.

    • Doua Bakry
    • , Ronald Grant
    • , Paul C Nathan
    • , Sarah Alexander
    • , Simon C Ling
    • , Annie Huang
    • , M Stephen Meyn
    • , David Malkin
    • , Eric Bouffet
    •  & Uri Tabori
  16. Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

    • Jordan Lerner-Ellis
  17. Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel-Aviv, Israel.

    • Rina Dvir
    •  & Ronit Elhasid
  18. Saint George Hospital University Medical Center, Beirut, Lebanon.

    • Roula Farah
  19. Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

    • Glenn P Taylor
    •  & Cynthia Hawkins
  20. The Gilbert Israeli Neurofibromatosis Center, Tel Aviv Medical Center, Tel Aviv, Israel.

    • Shay Ben-Shachar
  21. Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Simon C Ling
    •  & Carol Durno
  22. The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Steven Gallinger
    • , Carol Durno
    •  & Melyssa Aronson
  23. Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Steven Gallinger
  24. Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel Aviv Medical Center, Tel Aviv, Israel.

    • Shlomi Constantini
  25. Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Peter Dirks
    •  & Michael D Taylor
  26. The McLaughlin Centre, University of Toronto, Toronto, Canada.

    • Stephen W Scherer
  27. Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, UK.

    • Richard G Grundy
  28. Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • M Stephen Meyn
  29. Department of Haematology, University of Cambridge, Cambridge, UK.

    • Peter J Campbell


  1. for the Biallelic Mismatch Repair Deficiency Consortium

    A list of contributing members appears in the Supplementary Note.


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A.S., E.B., C.H., P.J.C. and U.T. designed the study. B.B.C., A.P., T.L., A.H., S.D., N.A., B.M., M.G., Y.H., D.M.M., M.R., Ma.R., G.B.P., N.P.T., K.P.H., E.E.H., A.Y.G., D.B., G.S.C., H.D., J.L.E. and M.M. performed experiments. A.S., B.B.C., R.B., L.B.A., Da.M., D.W., P.V.L., P.S.T., P.C., S.B., R.A., C.D., M.A. and U.T collected and analyzed data. R.G., R.D., Ro.G., R.E., R.F., G.P.T., P.C.N., S.A., S.B.-S., S.C.L., S.C., P.D., A.H. and U.T. provided reagents, tissue and clinical data. A.S., M.S.M., M.D.T., Z.F.P., C.E.P., D.M., P.J.C. and U.T. wrote the manuscript. S.G., S.W.S., C.D., M.A., A.G., M.S.M., M.D.T., Z.F.P., C.E.P., D.M., P.A.F., M.R.S., E.B., C.H. and P.J.C. provided technical support and conceptual advice. All authors approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Adam Shlien or Peter J Campbell or Uri Tabori.

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Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–13, Supplementary Tables 1 and 3, and Supplementary Note.

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  1. 1.

    Supplementary Table 2

    Nonsynonymous somatic mutations in ultra-hypermutated cancers (VAF >5%).

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