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Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia

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Listed:
  • Brenton G. Mar

    (Dana Farber Cancer Institute
    Boston Children’s Hospital)

  • Lars B. Bullinger

    (University of Ulm)

  • Kathleen M. McLean

    (Dana Farber Cancer Institute)

  • Peter V. Grauman

    (Brigham and Women's Hospital, Harvard Medical School)

  • Marian H. Harris

    (Boston Children’s Hospital)

  • Kristen Stevenson

    (Biostatistics & Computational Biology, Dana Farber Cancer Institute)

  • Donna S. Neuberg

    (Biostatistics & Computational Biology, Dana Farber Cancer Institute)

  • Amit U. Sinha

    (Memorial Sloan-Kettering Cancer Center)

  • Stephen E. Sallan

    (Dana Farber Cancer Institute
    Boston Children’s Hospital)

  • Lewis B. Silverman

    (Dana Farber Cancer Institute
    Boston Children’s Hospital)

  • Andrew L. Kung

    (Columbia University Medical Center)

  • Luca Lo Nigro

    (Oncoematologia Pediatrica, Azienda Policlinico OVE)

  • Benjamin L. Ebert

    (Brigham and Women's Hospital, Harvard Medical School)

  • Scott A. Armstrong

    (Memorial Sloan-Kettering Cancer Center)

Abstract

Relapsed paediatric acute lymphoblastic leukaemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis–remission–relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signalling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance.

Suggested Citation

  • Brenton G. Mar & Lars B. Bullinger & Kathleen M. McLean & Peter V. Grauman & Marian H. Harris & Kristen Stevenson & Donna S. Neuberg & Amit U. Sinha & Stephen E. Sallan & Lewis B. Silverman & Andrew L, 2014. "Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia," Nature Communications, Nature, vol. 5(1), pages 1-6, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4469
    DOI: 10.1038/ncomms4469
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