Mutational dynamics between primary and relapse neuroblastomas

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.A.S., S.R. and S.L. acknowledge the support of the Deutsche Forschungsgemeinschaft (DFG) within Collaborative Research Center SFB876, 'Providing Information by Resource-Constrained Analysis', subproject C1. J.K. and S.R. acknowledge support from the Mercator Foundation for project MERCUR Pe-2013-0012 (UA Ruhr Professorship 'Computational Biology'). M.F. was funded by German Cancer Aid (grant 110122), the Kinderkrebs-Neuroblastomforschung Fordergesellschaft and the Center for Molecular Medicine Cologne (CMMC). A.S., A. Eggert, M.F. and J.H.S. were supported by the German Ministry of Science and Education (BMBF) as part of the e:Med initiative (grant 01ZX1303A,B; 01ZX1307C,D,E; and 01ZX1307). A. Eggert and J.H.S. were supported by the ASSET consortium funded by the European Union (Framework Programme 7, grant 259348). A. Eggert was supported by the German Consortium for Translational Cancer Research (DKTK; joint funding pool and DKTK branch Berlin). A. Eggert and K. Astrahantseff were supported by the ENCCA consortium funded by the European Union (Framework Programme 7, grant 261474). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript