Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations

Abstract

The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas showed clonal evolution from the diagnostic tumor with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK signaling pathway. Seven events were detected only in the relapse tumor while the others showed clonal enrichment. In neuroblastoma cell lines we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18, 61%) and these lesions predicted for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide the rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

“…In addition, similar to previous studies (37,39), we identified some unique aberrations in the primary tumor that were no longer present in the relapse samples. These aberrations may tell us about their minor impact concerning driving the tumor cell progression and chemoresistance.…”

“…Temporal heterogeneity concerning copy-number changes and gene mutations was reported in neuroblastoma (37)(38)(39). In line with the studies performed on matched primary and relapse neuroblastomas, despite a decrease in subclonal copynumber changes in the relapse samples compared with the primary tumors (39), a number of de novo aberrations were found in the relapse samples (37,39).…”

“…In line with the studies performed on matched primary and relapse neuroblastomas, despite a decrease in subclonal copynumber changes in the relapse samples compared with the primary tumors (39), a number of de novo aberrations were found in the relapse samples (37,39). The question arises whether the accumulation of these new aberrations in the relapse clone was a result of selective pressure exerted by drug exposure or not.…”

NDPKA is not just a metastasis suppressor – be aware of its metastasis-promoting role in neuroblastoma

“…It has been reported that recurrent mutations affect pathways such as focal adhesions, Rac/Rho, RAS-MAPK, and YAP in advanced and relapsed neuroblastomas. 3,[40][41][42] Among these pathways, the Rac/Rho pathway is pertinent to the current knowledge of the NDPK-A network.…”

Considerations for the Development of Innovative Therapies Against Aggressive Neuroblastoma: Immunotherapy and Twist1 Targeting

“…Therefore, NB (and others pediatric cancers) can be compared with resistant to immune checkpoint inhibitors in adult cancers and need to be treated as such. First, while pediatric tumors demonstrate low mutation burdens at diagnosis, increases in mutation frequency can be enhanced after exposure to chemotherapy or radiotherapy [6,7]. In addition to increase neoantigens, radiation may increase immune response to checkpoint blockade as localized radiation along with checkpoint blockade resulted in an abscopal effect with regression of metastatic lesions outside of the radiation field [8].…”