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.
Highlights
Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes
We aggregated data from 702 neuroblastomas (679 diagnosis and 23 relapsed), which were profiled by whole genome sequencing (WGS, n = 205), whole exome sequencing (WES, n = 539), and/ or RNA-Seq (n = 169); 45% of the samples (n = 317) were new data generated from Children’s Oncology Group (COG) for this study (Supplementary Fig. 1a; the 317 samples were sequenced by WES plus targeted sequencing of the entire ATRX gene to detect structural variants along with sequence mutations)
Single-nucleotide variants, indels, and segmental chromosome copy alterations were analyzed for all 685 samples with WGS or WES; structural variants and focal copy alterations were analyzed for the 205 samples with WGS; and ATRX was considered comprehensively analyzed in all 205 WGS cases as well as 317 WES cases with ATRX targeted sequencing
Summary
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. The SHANK2 tumor suppressor is frequently disrupted by structural variants[8], TERT activating alterations frequently occur in high-risk neuroblastoma[9], and ATRX inactivation occurs in a large proportion of adolescent and young adult neuroblastomas but rarely in those arising from younger patients[10]. To better understand neuroblastoma pathogenesis, here we analyze whole-genome, whole-exome, and/or transcriptome sequencing data of 702 neuroblastomas comprised of all age and risk groups, assembled from the St. Jude/Washington University Pediatric Cancer Genome Project (PCGP), the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) project, and 317 additional samples from the Children’s Oncology Group (COG). Jude/Washington University Pediatric Cancer Genome Project (PCGP), the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) project, and 317 additional samples from the Children’s Oncology Group (COG) Such a design allows identification of ageassociated molecular aberrations in this developmental malignancy. The size of the cohort allows identification of rare driver events
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