FOXR2 activation

FOXR2 gene expression is observed in approximately 8% of neuroblastoma cases. FOXR2 gene expression is normally absent postnatally, with the exception of male reproductive tissues.[34] FOXR2 expression is also observed in a subset of central nervous system (CNS) primitive neuroectodermal tumors, termed CNS NB-FOXR2.[35] FOXR2 overexpression was virtually mutually exclusive in neuroblastoma tumors with both elevated MYC and MYCN expression. Although MYCN gene expression was not elevated in neuroblastoma with FOXR2 activation, the gene expression profile for the FOXR2 expressing cases closely resembled that of MYCN-amplified neuroblastoma. FOXR2 binds MYCN and appears to stabilize the MYCN protein, leading to high levels of MYCN protein in neuroblastoma with FOXR2 activation. This finding provides an explanation for the similar gene expression profiles for neuroblastoma with FOXR2 activation and neuroblastoma with MYCN amplification.

Neuroblastoma with FOXR2 activation is observed at comparable rates in high-risk and non–high-risk cases.[34] Among high-risk cases, outcomes for patients whose tumors showed FOXR2 activation were similar to those for cases with MYCN amplification. In a multivariable analysis, FOXR2 activation was significantly associated with inferior OS, along with INSS stage 4, age 18 months or older, and MYCN amplification.