Abstract
Simple SummaryNeuroblastoma is a pediatric cancer that arises in the sympathetic nervous system. High-risk neuroblastoma is clinically challenging and identification of novel therapies, particularly those that offer a reduction in morbidity for these patients, is a high priority. Combining genetic analyses with investigation of molecular mechanisms, while considering recent advances in our understanding of key developmental events, provides avenues for future treatment. Here we review and highlight several recently published articles that address novel molecular mechanisms arising from chromosome 1p, 2p, and 11q aberrations, which likely contribute to high-risk neuroblastoma, and discusses their potential impact on treatment options. Neuroblastoma is the most common extracranial solid pediatric tumor, with around 15% childhood cancer-related mortality. High-risk neuroblastomas exhibit a range of genetic, morphological, and clinical heterogeneities, which add complexity to diagnosis and treatment with existing modalities. Identification of novel therapies is a high priority in high-risk neuroblastoma, and the combination of genetic analysis with increased mechanistic understanding—including identification of key signaling and developmental events—provides optimism for the future. This focused review highlights several recent findings concerning chromosomes 1p, 2p, and 11q, which link genetic aberrations with aberrant molecular signaling output. These novel molecular insights contribute important knowledge towards more effective treatment strategies for neuroblastoma.
Highlights
Uses a classification system based on several key criteria that include age, stage, tumor histology, MYCN amplification (MNA), 11q-deletion, and ploidy to define very low, low, intermediate- and high-risk groups according to 5-year event-free survival (EFS) [20,21]
Siaw et al were able to show that overexpression of DLG2 in neuroblastoma cell lines reduced their proliferation and led to an increased transcription of adrenal specific genes, promoting differentiation to a more chromaffin-like cell type. They could show that Anaplastic Lymphoma Kinase (ALK)/MAPK signaling suppressed DLG2 transcription, suggesting that oncogenic ALK/MAPK activity blocks differentiation cues through regulation of key components such as DLG2. This mechanistic explanation of a role for DLG2 as a tumor suppressor was accompanied by a comprehensive genetic analysis of 120 11q-deleted neuroblastoma cases that was able to identify DLG2 as the most proximal gene in the shortest region of genetic overlap in patient material, with DLG2 disrupted in all 11q deleted cases examined [21]
In addition to considering the loss of DNA damage response (DDR) factors, which decrease genomic integrity [101], it is clear that tumor suppressors, such as DLG2, are influenced by oncogenic signaling activity
Summary
The chromaffin cells of the adrenal medulla arise from migratory neural crest cell derived sympathoadrenal precursor cells (Figure 1). These cells originate from the dorsal neuroepithelium and migrate to the vicinity of the dorsal aorta. Lineage-tracing experiments in mice have revealed that chromaffin cells in the adrenal gland arise mostly from embryonic nerveassociated cells ofcells neural crestadrenal origin named. RNA that chromaffin in the gland arise mostly embryonic nerve-associated sequencing of the transcriptome from developing human and mouse adrenal glands, as cells of neural crest origin named Schwann cell precursors [8]. Single-cell RNA sequencing well as transcriptome from low versus risk neuroblastoma samples, has further our of the fromhigh developing human and mouse adrenal glands, increased as well as from knowledge developmental trajectories and cellular statesincreased in neuroblastoma [8,9,10,11].of low versusofhigh risk neuroblastoma samples, has further our knowledge developmental trajectoriestransition and cellular states in neuroblastoma [8,9,10,11]
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