Introduction

Neuroblastoma, an embryonal tumor of the sympathetic nervous system, is the most common extra-cranial solid tumor of childhood and the third leading cause of childhood cancer-related mortality (1,2). With a median age at diagnosis of 17 months, neuroblastoma has an annual age-adjusted incidence rate of 10.0 per million children younger than 15 years (2,3). It arises from postganglionic sympathetic neuroblasts, typically involving the adrenal medulla or paraspinal ganglia, and clinical presentations range from the incidental detection of an isolated, asymptomatic mass to disseminated disease in which children often present with rapid clinical deterioration.

The hallmark of neuroblastoma is its distinctive clinical heterogeneity. Most infants have tumors which undergo spontaneous regression or behave in a benign manner, with survival rates exceeding 95%, despite disease that may involve the liver, skin, and bone marrow (4–6). In contrast, older children with high-risk neuroblastoma have aggressive disease that is often resistant to intensive multi-modality therapy (7). There is abundant evidence that these divergent neuroblastoma phenotypes are predicted by distinct molecular features that are prognostic of survival outcomes and currently guide therapeutic decisions in the broad sense of defining tumor aggressiveness (8). The unmet need in the field, as discussed herein, is to precisely define molecular genetic subsets of high-risk neuroblastoma that reliably predict unique oncogenic vulnerabilities that are exploitable therapeutically.