Letter | Published:

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

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD). J. Med. Genet. 51, 355–365 (2014).

  2. 2.

    et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

  3. 3.

    et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat. Genet. 9, 48–55 (1995).

  4. 4.

    et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat. Genet. 46, 444–450 (2014).

  5. 5.

    , , , & Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2. Proc. Natl. Acad. Sci. USA 94, 3122–3127 (1997).

  6. 6.

    , & Heteroduplex repair in extracts of human HeLa cells. J. Biol. Chem. 266, 3744–3751 (1991).

  7. 7.

    , , , & Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSbeta, but clustered slip-outs are poorly repaired. Proc. Natl. Acad. Sci. USA 107, 12593–12598 (2010).

  8. 8.

    & DNA polymerase epsilon and its roles in genome stability. IUBMB Life 66, 339–351 (2014).

  9. 9.

    , & DNA replication fidelity and cancer. Semin. Cancer Biol. 20, 281–293 (2010).

  10. 10.

    , & The high fidelity and unique error signature of human DNA polymerase epsilon. Nucleic Acids Res. 39, 1763–1773 (2011).

  11. 11.

    & Analyzing fidelity of DNA polymerases. Methods Enzymol. 262, 217–232 (1995).

  12. 12.

    et al. Phenotypic characterization of missense polymerase-delta mutations using an inducible protein-replacement system. Nat. Commun. 5, 4990 (2014).

  13. 13.

    et al. Mutation at the polymerase active site of mouse DNA polymerase delta increases genomic instability and accelerates tumorigenesis. Mol. Cell. Biol. 27, 7669–7682 (2007).

  14. 14.

    et al. Active site mutations in mammalian DNA polymerase delta alter accuracy and replication fork progression. J. Biol. Chem. 285, 32264–32272 (2010).

  15. 15.

    , , , & Division of labor at the eukaryotic replication fork. Mol. Cell 30, 137–144 (2008).

  16. 16.

    et al. Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition. Genome Res. 24, 1751–1764 (2014).

  17. 17.

    Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  18. 18.

    et al. Integrated genomic characterization of endometrial carcinoma. Nature 497, 67–73 (2013).

  19. 19.

    et al. Oncologic surveillance for subjects with biallelic mismatch repair gene mutations: 10 year follow-up of a kindred. Pediatr. Blood Cancer 59, 652–656 (2012).

  20. 20.

    et al. A single-nucleotide substitution mutator phenotype revealed by exome sequencing of human colon adenomas. Cancer Res. 72, 6279–6289 (2012).

  21. 21.

    et al. Comparative lesion sequencing provides insights into tumor evolution. Proc. Natl. Acad. Sci. USA 105, 4283–4288 (2008).

  22. 22.

    et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012).

  23. 23.

    et al. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur. J. Cancer 50, 987–996 (2014).

  24. 24.

    & Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

  25. 25.

    & Improved variant discovery through local re-alignment of short-read next-generation sequencing data using SRMA. Genome Biol. 11, R99 (2010).

  26. 26.

    et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

  27. 27.

    et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013).

  28. 28.

    et al. Tissue-specific mismatch repair protein expression: MSH3 is higher than MSH6 in multiple mouse tissues. DNA Repair (Amst.) 12, 46–52 (2013).

  29. 29.

    et al. Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication. Genome Res. 24, 1740–1750 (2014).

Download references

Acknowledgements

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.

Affiliations

  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

Consortia

  1. for the Biallelic Mismatch Repair Deficiency Consortium

    A list of contributing members appears in the Supplementary Note.

Authors

  1. Search for Adam Shlien in:

  2. Search for Brittany B Campbell in:

  3. Search for Richard de Borja in:

  4. Search for Ludmil B Alexandrov in:

  5. Search for Daniele Merico in:

  6. Search for David Wedge in:

  7. Search for Peter Van Loo in:

  8. Search for Patrick S Tarpey in:

  9. Search for Paul Coupland in:

  10. Search for Sam Behjati in:

  11. Search for Aaron Pollett in:

  12. Search for Tatiana Lipman in:

  13. Search for Abolfazl Heidari in:

  14. Search for Shriya Deshmukh in:

  15. Search for Na'ama Avitzur in:

  16. Search for Bettina Meier in:

  17. Search for Moritz Gerstung in:

  18. Search for Ye Hong in:

  19. Search for Diana M Merino in:

  20. Search for Manasa Ramakrishna in:

  21. Search for Marc Remke in:

  22. Search for Roland Arnold in:

  23. Search for Gagan B Panigrahi in:

  24. Search for Neha P Thakkar in:

  25. Search for Karl P Hodel in:

  26. Search for Erin E Henninger in:

  27. Search for A Yasemin Göksenin in:

  28. Search for Doua Bakry in:

  29. Search for George S Charames in:

  30. Search for Harriet Druker in:

  31. Search for Jordan Lerner-Ellis in:

  32. Search for Matthew Mistry in:

  33. Search for Rina Dvir in:

  34. Search for Ronald Grant in:

  35. Search for Ronit Elhasid in:

  36. Search for Roula Farah in:

  37. Search for Glenn P Taylor in:

  38. Search for Paul C Nathan in:

  39. Search for Sarah Alexander in:

  40. Search for Shay Ben-Shachar in:

  41. Search for Simon C Ling in:

  42. Search for Steven Gallinger in:

  43. Search for Shlomi Constantini in:

  44. Search for Peter Dirks in:

  45. Search for Annie Huang in:

  46. Search for Stephen W Scherer in:

  47. Search for Richard G Grundy in:

  48. Search for Carol Durno in:

  49. Search for Melyssa Aronson in:

  50. Search for Anton Gartner in:

  51. Search for M Stephen Meyn in:

  52. Search for Michael D Taylor in:

  53. Search for Zachary F Pursell in:

  54. Search for Christopher E Pearson in:

  55. Search for David Malkin in:

  56. Search for P Andrew Futreal in:

  57. Search for Michael R Stratton in:

  58. Search for Eric Bouffet in:

  59. Search for Cynthia Hawkins in:

  60. Search for Peter J Campbell in:

  61. Search for Uri Tabori in:

Contributions

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.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

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

Excel files

  1. 1.

    Supplementary Table 2

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

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.3202

Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing