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.
|Grant||This work was funded by the The Netherlands Organisation for Scientific Research (NWO); grant id nwo/639.072.309 - Statistical Models for Structural Genetic Variants in the Genome of the Netherlands|
Schramm, A. (Alexander), Köster, J, Assenov, Y. (Yassen), Althoff, K. (Kristina), Peifer, M. (Martin), Mahlow, E. (Ellen), … Schulte, J.H. (Johannes). (2015). Mutational dynamics between primary and relapse neuroblastomas. Nature Genetics, 47(8), 872–877. doi:10.1038/ng.3349