Genetic and Histopathological Heterogeneity of Neuroblastoma and Precision Therapeutic Approaches for Extremely Unfavorable Histology Subgroups

Abstract

Peripheral neuroblastic tumors (neuroblastoma, ganglioneuroblastoma and ganglioneuroma) are heterogeneous and their diverse and wide range of clinical behaviors (spontaneous regression, tumor maturation and aggressive progression) are closely associated with genetic/molecular properties of the individual tumors. The International Neuroblastoma Pathology Classification, a biologically relevant and prognostically significant morphology classification distinguishing the favorable histology (FH) and unfavorable histology (UH) groups in this disease, predicts survival probabilities of the patients with the highest hazard ratio. The recent advance of neuroblastoma research with precision medicine approaches demonstrates that tumors in the UH group are also heterogeneous and four distinct subgroups—MYC, TERT, ALT and null—are identified. Among them, the first three subgroups are collectively named extremely unfavorable histology (EUH) tumors because of their highly aggressive clinical behavior. As indicated by their names, these EUH tumors are individually defined by their potential targets detected molecularly and immunohistochemically, such as MYC-family protein overexpression, TERT overexpression and ATRX (or DAXX) loss. In the latter half on this paper, the current status of therapeutic targeting of these EUH tumors is discussed for the future development of effective treatments of the patients.

Analysis of High-Risk Neuroblastoma Transcriptome Reveals Gene Co-Expression Signatures and Functional Features

“…Adrenal gland samples are clustered together, too, showing low counts in the genes highly expressed in neuroblastoma ( Figure 2 a), meaning the expression patterns of these two types of samples are different from each other, which proves the power of transcriptome analysis in detecting the difference in gene expression between tumor and normal samples. We also saw that the behavior of the expression of neuroblastoma may differ between patients ( Figure 2 a,b), and this can be explained by the individual genetic features of neuroblastoma in each patient and demonstrates the high heterogeneity that we can find in gene expression across tumor samples of this type [ 42 ].…”

Spinal ganglioneuroma with extension to the brachial plexus. The challenges for total surgical excision, a case report

“…This is biologically relevant and prognostically significant classification distinguishing the two classifications and predicts survival. Ganglioneuromas are classified into favorable histology group [ 3 ].…”

The relationship between contrast-enhanced computed tomography radiomics features and mitosis karyorrhexis index in neuroblastoma

“…MKI refers to the proportion of cells exhibiting mitosis or nuclear fragmentation in a population of 5000 tumor cells. The three classifications based on MKI status are low-MKI, intermediate-MKI, and high-MKI [ 4 , 5 ]. Therefore, MKI can reflect the proliferation status of neuroblastoma cells.…”