Target Genes of c-MYC and MYCN with Prognostic Power in Neuroblastoma Exhibit Different Expressions during Sympathoadrenal Development

SIMPLE SUMMARY: More than 40% of high-risk neuroblastoma (NB) cases are characterized by aberrations in the transcription factors MYCN and c-MYC. Nevertheless, the developmental stage and mechanisms through which MYCN and c-MYC contribute to the onset and progression of the malignancy are not fully understood. In this study, we selected different c-MYC and MYCN targets with clinical or biological relevance and prognostic value to model multigene transcriptional risk scores. We found that the modeled scores accurately classify patients into groups with different outcomes, with high-risk-scoring patients exhibiting worse clinical features. Furthermore, target genes associated with poor prognosis showed a higher expression in sympathoblasts than in chromaffin cells during the sympathoadrenal development. ABSTRACT: Deregulation of the MYC family of transcription factors c-MYC (encoded by MYC), MYCN, and MYCL is prevalent in most human cancers, with an impact on tumor initiation and progression, as well as response to therapy. In neuroblastoma (NB), amplification of the MYCN oncogene and over-expression of MYC characterize approximately 40% and 10% of all high-risk NB cases, respectively. However, the mechanism and stage of neural crest development in which MYCN and c-MYC contribute to the onset and/or progression of NB are not yet fully understood. Here, we hypothesized that subtle differences in the expression of MYCN and/or c-MYC targets could more accurately stratify NB patients in different risk groups rather than using the expression of either MYC gene alone. We employed an integrative approach using the transcriptome of 498 NB patients from the SEQC cohort and previously defined c-MYC and MYCN target genes to model a multigene transcriptional risk score. Our findings demonstrate that defined sets of c-MYC and MYCN targets with significant prognostic value, effectively stratify NB patients into different groups with varying overall survival probabilities. In particular, patients exhibiting a high-risk signature score present unfavorable clinical parameters, including increased clinical risk, higher INSS stage, MYCN amplification, and disease progression. Notably, target genes with prognostic value differ between c-MYC and MYCN, exhibiting distinct expression patterns in the developing sympathoadrenal system. Genes associated with poor outcomes are mainly found in sympathoblasts rather than in chromaffin cells during the sympathoadrenal development.