期刊
NATURE GENETICS
卷 47, 期 8, 页码 872-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3349
关键词
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资金
- Deutsche Forschungsgemeinschaft (DFG) [SFB876]
- Mercator Foundation
- German Cancer Aid [110122]
- Kinderkrebs-Neuroblastomforschung Fordergesellschaft
- Center for Molecular Medicine Cologne (CMMC)
- German Ministry of Science and Education (BMBF) as part of the e:Med initiative [01ZX1303A,B, 01ZX1307C,D,E, 01ZX1307]
- ASSET consortium - European Union [259348]
- German Consortium for Translational Cancer Research (DKTK)
- ENCCA consortium - European Union [261474]
Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.
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