期刊
NATURE GENETICS
卷 45, 期 3, 页码 279-284出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2529
关键词
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资金
- US National Institutes of Health [CA98543, CA98413, RC1MD004418, CA124709, CA060104]
- National Human Genome Research Institute grant [U54HG003067]
- National Cancer Institute, US National Institutes of Health [HHSN261200800001E]
- Canadian Institutes of Health Research Fellowship
- Roman M. Babicki Fellowship in Medical Research at the University of British Columbia
- Canada Research Chair in Genome Science
- Giulio D'Angio Endowed Chair
- Alex's Lemonade Stand Foundation
- Arms Wide Open Foundation
- Cookies for Kids Foundation
Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per Mb (0.48 nonsilent) and notably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing a recurrent p.Pro44Leu alteration) and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1 and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies that rely on frequently altered oncogenic drivers.
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