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Pan-neuroblastoma analysis reveals age- and signature-associated driver alterations

Author

Listed:
  • Samuel W. Brady

    (St. Jude Children’s Research Hospital)

  • Yanling Liu

    (St. Jude Children’s Research Hospital)

  • Xiaotu Ma

    (St. Jude Children’s Research Hospital)

  • Alexander M. Gout

    (St. Jude Children’s Research Hospital)

  • Kohei Hagiwara

    (St. Jude Children’s Research Hospital)

  • Xin Zhou

    (St. Jude Children’s Research Hospital)

  • Jian Wang

    (St. Jude Children’s Research Hospital)

  • Michael Macias

    (St. Jude Children’s Research Hospital)

  • Xiaolong Chen

    (St. Jude Children’s Research Hospital)

  • John Easton

    (St. Jude Children’s Research Hospital)

  • Heather L. Mulder

    (St. Jude Children’s Research Hospital)

  • Michael Rusch

    (St. Jude Children’s Research Hospital)

  • Lu Wang

    (St. Jude Children’s Research Hospital)

  • Joy Nakitandwe

    (St. Jude Children’s Research Hospital)

  • Shaohua Lei

    (St. Jude Children’s Research Hospital)

  • Eric M. Davis

    (St. Jude Children’s Research Hospital)

  • Arlene Naranjo

    (Department of Biostatistics, University of Florida, Children’s Oncology Group Statistics & Data Center)

  • Cheng Cheng

    (St. Jude Children’s Research Hospital)

  • John M. Maris

    (Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania)

  • James R. Downing

    (St. Jude Children’s Research Hospital)

  • Nai-Kong V. Cheung

    (Memorial Sloan Kettering Cancer Center)

  • Michael D. Hogarty

    (Division of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania)

  • Michael A. Dyer

    (St. Jude Children’s Research Hospital)

  • Jinghui Zhang

    (St. Jude Children’s Research Hospital)

Abstract

Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. To better understand neuroblastoma pathogenesis, here we analyze whole-genome, whole-exome and/or transcriptome data from 702 neuroblastoma samples. Forty percent of samples harbor at least one recurrent driver gene alteration and most aberrations, including MYCN, ATRX, and TERT alterations, differ in frequency by age. MYCN alterations occur at median 2.3 years of age, TERT at 3.8 years, and ATRX at 5.6 years. COSMIC mutational signature 18, previously associated with reactive oxygen species, is the most common cause of driver point mutations in neuroblastoma, including most ALK and Ras-activating variants. Signature 18 appears early and is continuous throughout disease evolution. Signature 18 is enriched in neuroblastomas with MYCN amplification, 17q gain, and increased expression of mitochondrial ribosome and electron transport-associated genes. Recurrent FGFR1 variants in six patients, and ALK N-terminal structural alterations in five samples, identify additional patients potentially amenable to precision therapy.

Suggested Citation

  • Samuel W. Brady & Yanling Liu & Xiaotu Ma & Alexander M. Gout & Kohei Hagiwara & Xin Zhou & Jian Wang & Michael Macias & Xiaolong Chen & John Easton & Heather L. Mulder & Michael Rusch & Lu Wang & Joy, 2020. "Pan-neuroblastoma analysis reveals age- and signature-associated driver alterations," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18987-4
    DOI: 10.1038/s41467-020-18987-4
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    Cited by:

    1. Min Pan & Yinwen Zhang & William C. Wright & Xueying Liu & Barbara Passaia & Duane Currier & Jonathan Low & Richard H. Chapple & Jacob A. Steele & Jon P. Connelly & Bensheng Ju & Emily Plyler & Meifen, 2025. "Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    2. Karin Schmelz & Joern Toedling & Matt Huska & Maja C. Cwikla & Louisa-Marie Kruetzfeldt & Jutta Proba & Peter F. Ambros & Inge M. Ambros & Sengül Boral & Marco Lodrini & Celine Y. Chen & Martin Burker, 2021. "Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Perla Pucci & Liam C. Lee & Miaojun Han & Jamie D. Matthews & Leila Jahangiri & Michaela Schlederer & Eleanor Manners & Annabel Sorby-Adams & Joshua Kaggie & Ricky M. Trigg & Christopher Steel & Lucy , 2024. "Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Min Pan & William C. Wright & Richard H. Chapple & Asif Zubair & Manbir Sandhu & Jake E. Batchelder & Brandt C. Huddle & Jonathan Low & Kaley B. Blankenship & Yingzhe Wang & Brittney Gordon & Payton A, 2021. "The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.

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