A Novel Prognostic Metric Resolves the MYCN enigma in Silico and Points to a Biosynthetic Regulatory Shift Driven by MYCN Amplification in Neuroblastoma

Abstract

Neuroblastoma (NB) is the most common extra-cranial solid tumour in children. Although MYCN amplification is typically indicative of a poor prognosis, the expression level of MYCN has a non-monotonic relationship with the clinical outcome. This paper proposes an explanation for this phenomenon, which is called the MYCN enigma in the literature. The p53/MYCN metric, which is a measure of the p53 protein level relative to the MYCN protein level in a NB tumour, is the key concept. Our hypothesis is that the metric has a positive relationship with the outcome of a patient. It is presented as a binary classification system, where the prognosis is favourable when p53/MYCN>3.5. The mathematical model presented in this paper describes the dynamics between MYCN, p53, ARF, and MDM2; their genes; and their mRNA transcripts. Simulations were carried out by solving the model numerically in a series of initial value problems. The results are aligned with a list of clinical and experimental observations. We extracted association rules with the Apriori algorithm and explored the parametric space stochastically. Assuming that MYCN enables biogenesis in NB tumours, our results support the prediction that MYCN amplification shifts the balance towards producing MYCN. When a wild-type tumour is deficient in MYCN, stress responses may restore biogenesis in general and preferentially produce MYCN in a negative feedback loop. Another prediction is that MYCN - amplified tumours, without treatment, require hard-to-attain biosynthetic rates and stress responses to achieve good outcomes.