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

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 Nakitandwe, Shaohua Lei, Eric M. Davis, Arlene Naranjo, Cheng Cheng, John M. Maris, James R. Downing, Nai-Kong V. Cheung, Michael D. Hogarty (), Michael A. Dyer () and Jinghui Zhang ()
Additional contact information
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

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18987-4

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