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The acquisition of molecular drivers in pediatric therapy-related myeloid neoplasms

Author

Listed:
  • Jason R. Schwartz

    (Vanderbilt University Medical Center, Department of Pediatrics)

  • Jing Ma

    (St. Jude Children’s Research Hospital, Department of Pathology)

  • Jennifer Kamens

    (Stanford University School of Medicine, Department of Pediatrics)

  • Tamara Westover

    (St. Jude Children’s Research Hospital, Department of Pathology)

  • Michael P. Walsh

    (St. Jude Children’s Research Hospital, Department of Pathology)

  • Samuel W. Brady

    (St. Jude Children’s Research Hospital, Department of Computational Biology)

  • J. Robert Michael

    (St. Jude Children’s Research Hospital, Department of Computational Biology)

  • Xiaolong Chen

    (St. Jude Children’s Research Hospital, Department of Computational Biology)

  • Lindsey Montefiori

    (St. Jude Children’s Research Hospital, Department of Pathology)

  • Guangchun Song

    (St. Jude Children’s Research Hospital, Department of Pathology)

  • Gang Wu

    (St. Jude Children’s Research Hospital, Department of Computational Biology)

  • Huiyun Wu

    (St. Jude Children’s Research Hospital, Department of Biostatistics)

  • Cristyn Branstetter

    (Arkansas Children’s Northwest Hospital, Department of Hematology/Oncology)

  • Ryan Hiltenbrand

    (St. Jude Children’s Research Hospital, Department of Pathology)

  • Michael F. Walsh

    (Memorial Sloan Kettering Cancer Center, Department of Pediatrics)

  • Kim E. Nichols

    (St. Jude Children’s Research Hospital, Department of Oncology)

  • Jamie L. Maciaszek

    (St. Jude Children’s Research Hospital, Department of Oncology)

  • Yanling Liu

    (St. Jude Children’s Research Hospital, Department of Computational Biology)

  • Priyadarshini Kumar

    (St. Jude Children’s Research Hospital, Department of Pathology)

  • John Easton

    (St. Jude Children’s Research Hospital, Department of Computational Biology)

  • Scott Newman

    (St. Jude Children’s Research Hospital, Department of Computational Biology)

  • Jeffrey E. Rubnitz

    (St. Jude Children’s Research Hospital, Department of Oncology)

  • Charles G. Mullighan

    (St. Jude Children’s Research Hospital, Department of Pathology)

  • Stanley Pounds

    (St. Jude Children’s Research Hospital, Department of Biostatistics)

  • Jinghui Zhang

    (St. Jude Children’s Research Hospital, Department of Computational Biology)

  • Tanja Gruber

    (Stanford University School of Medicine, Department of Pediatrics
    Stanford University School of Medicine, Stanford Cancer Institute)

  • Xiaotu Ma

    (St. Jude Children’s Research Hospital, Department of Computational Biology)

  • Jeffery M. Klco

    (St. Jude Children’s Research Hospital, Department of Pathology)

Abstract

Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis. The somatic and germline genomic alterations that drive these myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 84 pediatric tMN cases (tMDS: n = 28, tAML: n = 56). Our data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements are frequent somatic drivers, and we identify cases with aberrant MECOM expression secondary to enhancer hijacking. Unlike adults with tMN, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases are unrelated clones arising as a consequence of cytotoxic therapy. These studies also uncover rare cases of lineage switch disease rather than true secondary neoplasms.

Suggested Citation

  • Jason R. Schwartz & Jing Ma & Jennifer Kamens & Tamara Westover & Michael P. Walsh & Samuel W. Brady & J. Robert Michael & Xiaolong Chen & Lindsey Montefiori & Guangchun Song & Gang Wu & Huiyun Wu & C, 2021. "The acquisition of molecular drivers in pediatric therapy-related myeloid neoplasms," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21255-8
    DOI: 10.1038/s41467-021-21255-8
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    Cited by:

    1. Eline J. M. Bertrums & Jurrian K. Kanter & Lucca L. M. Derks & Mark Verheul & Laurianne Trabut & Markus J. Roosmalen & Henrik Hasle & Evangelia Antoniou & Dirk Reinhardt & Michael N. Dworzak & Nora Mü, 2024. "Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Yanling Liu & Jonathon Klein & Richa Bajpai & Li Dong & Quang Tran & Pandurang Kolekar & Jenny L. Smith & Rhonda E. Ries & Benjamin J. Huang & Yi-Cheng Wang & Todd A. Alonzo & Liqing Tian & Heather L., 2023. "Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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