A mechanistic classification of clinical phenotypes in neuroblastoma

Abstract

Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance–negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.

Neuroblastoma stage 4S: Tumor regression rate and risk factors of progressive disease

“…However, in the ongoing European LINES trial, the effect of the CNA in this group is being prospectively studied. Recent research concluded that the combination of telomere maintenance activity and aberrations in the RAS and TP53 pathways can predict unfavorable outcome in low‐risk patients . It would be interesting to see if these parameters are helpful in making treatment decisions.…”

Study of chromatin remodeling genes implicates SMARCA4 as a putative player in oncogenesis in neuroblastoma

“…Correlations between the presence of variations in CRG/EMG and other genetic factors associated with poor outcome in NB should be determined in future studies and larger series, such as the overall mutational burden 50 or factors contributing to a mechanistical classification of NB including mutations of the RAS: MAPK pathway and telomere maintenance mechanisms. 51 New treatment strategies are necessary for patients with high-risk NB, and our data further highlight the potential interest of drugs modulating chromatin remodeling processes. Histone deacetylase inhibitors (HDACi) or DNA methyltransferase inhibitors were the first epigenetic compounds to reach clinical trials with potential benefits in some patients with CRG/EMG variations.…”

“…This suggests that cases harboring CRG/EMG variations might present more aggressive disease or that salvage treatment used at relapse might potentially be more efficient in cases showing no CRG/EMG variation. Correlations between the presence of variations in CRG/EMG and other genetic factors associated with poor outcome in NB should be determined in future studies and larger series, such as the overall mutational burden or factors contributing to a mechanistical classification of NB including mutations of the RAS:MAPK pathway and telomere maintenance mechanisms …”

A new risk score for patients after first recurrence of stage 4 neuroblastoma aged ≥18 months at first diagnosis

“…The five described variables appear to cover the impact of MYCN oncogene ( MYCN ) amplification, increased lactate dehydrogenase levels, and other risk factors mentioned. In the future, novel omics technologies may provide better insights into the molecular mechanism and potentially better explain clinical courses right from the first diagnosis . Tumor material for molecular investigations was not available in most cases of this series.…”

“…In the future, novel omics technologies may provide better insights into the molecular mechanism and potentially better explain clinical courses right from the first diagnosis. 13,14 Tumor material for molecular investigations was not available in most cases of this series. The match of phenotype and genotype is an important task for the future.…”