The Machine-Learning-Mediated Interface of Microbiome and Genetic Risk Stratification in Neuroblastoma Reveals Molecular Pathways Related to Patient Survival

SIMPLE SUMMARY: Neuroblastoma is a highly heterogeneous malignancy with a wide range of outcomes from spontaneous regression to fatal chemoresistant disease, as currently treated according to the risk stratification of the Children’s Oncology Group (COG), resulting in some high COG risk patients receiving excessive treatment, due to lacking predictors for treatment response. Here, we sought to complement COG risk classification by using the tumor intracellular microbiome, which is part of the tumor’s molecular signature. We determine that an intra-tumor microbial gene abundance score, namely M-score, separates the high COG-risk patients into two subpopulations (M(high) and M(low)) with higher accuracy in risk stratification than the current COG risk assessment, thus sparing a subset of high COG-risk patients from being subjected to traditional high-risk therapies. ABSTRACT: Currently, most neuroblastoma patients are treated according to the Children’s Oncology Group (COG) risk group assignment; however, neuroblastoma’s heterogeneity renders only a few predictors for treatment response, resulting in excessive treatment. Here, we sought to couple COG risk classification with tumor intracellular microbiome, which is part of the molecular signature of a tumor. We determine that an intra-tumor microbial gene abundance score, namely M-score, separates the high COG-risk patients into two subpopulations (M(high) and M(low)) with higher accuracy in risk stratification than the current COG risk assessment, thus sparing a subset of high COG-risk patients from being subjected to traditional high-risk therapies. Mechanistically, the classification power of M-scores implies the effect of CREB over-activation, which may influence the critical genes involved in cellular proliferation, anti-apoptosis, and angiogenesis, affecting tumor cell proliferation survival and metastasis. Thus, intracellular microbiota abundance in neuroblastoma regulates intracellular signals to affect patients’ survival.