Genomic Analysis Identifies Mutation Dynamics in Relapsed Neuroblastoma

Although children with neuroblastoma often initially respond to therapy, lethal resistant tumors recur in the majority of patients. Large-scale sequencing studies have highlighted the low mutation burden of primary neuroblastoma tumors; however, little is known about the genetic alterations that mediate neuroblastoma recurrence. Using integrated genomic profiling of 16 paired primary and relapse neuroblastoma samples, Schramm and colleagues found that, whereas there was no change in promoter methylation patterns, relapse tumors exhibited an altered transcriptome profile, a significant increase in the number of mutations and chromosomal copy-number changes, and a shift in mutation signatures compared with primary tumors. Clonal selection resulted in decreased subclonal heterogeneity and the enrichment of relapse-specific recurrent mutations in the putative CHD5 tumor suppressor, DOCK8, and PTPN14, the latter of which was associated with activation of Hippo–YAP signaling in vitro. In addition, mutations in genes implicated in cell–cell interactions and epithelial–mesenchymal transition (EMT) were detected in 13 of 16 relapse tumors. Consistent with these findings, Eleveld, Oldridge, Bernard, and colleagues performed whole-genome sequencing of 23 paired primary and relapse neuroblastoma tumors and found an increased burden of mutations and structural aberrations, evidence for subclonal outgrowth, and the acquisition of relapse-specific somatic mutations in relapse tumors. In particular, 18 of 23 relapse tumors displayed mutations or structural alterations in genes associated with activation of RAS–MAPK signaling, including BRAF, PTPN11, ALK, and NF1; a subset of these mutations were present in the primary tumors and showed relapse-specific enrichment, whereas seven mutations were uniquely detected in relapse tumors. Of note, the presence of mutations in NF1, BRAF, or RAS genes was associated with sensitivity to MEK inhibitors both in neuroblastoma cell lines and xenograft models. These findings provide insight into the genomic landscape of relapse neuroblastoma and suggest that genomic analysis of relapse tumor biopsies may enable selection of targeted therapies.

Schramm A, Köster J, Assenov Y, Althoff K, Peifer M, Mahlow E, et al. Mutational dynamics between primary and relapse neuroblastomas. Nat Genet 2015 Jun 29 [Epub ahead of print].

Eleveld TF, Oldridge DA, Bernard V, Koster J, Daage LC, Diskin SJ, et al. Relapsed neuroblastomas show frequent RAS–MAPK pathway mutations. Nat Genet 2015 Jun 29 [Epub ahead of print].