In a study reported in the Journal of Clinical Oncology, Schmitt-Hoffner et al found that FOXR2 expression is associated with poorer survival in neuroblastoma, identifying a subgroup of patients in addition to those with MYCN-amplified tumors who are at risk of unfavorable outcomes. They found that FOXR2 stabilization of MYCN protein results in an increase in MYCN levels, representing a mechanism of increasing such levels in the absence of MYCN amplification.
Study Details
The study involved analysis of three independent transcriptional data sets representing a total of 1,030 primary neuroblastomas. Tumor samples were assessed for protein levels of FOXR2 and MYCN. Immunoprecipitation was performed for FOXR2 and MYCN, and FOXR2 expression was silenced in two neuroblastoma cell lines to examine the effects on cellular processes, transcriptional factors, and MYCN protein levels.
Key Findings
In the combined data sets, 9% of tumors exhibited FOXR2 expression, accompanied by low levels of MYCN mRNA.
Analysis in two data sets (n = 498 and n = 283; 8% and 6% with FOXR2 expression) showed that patients with FOXR2 expression had significantly poorer (P < .001 in both) 10-year overall survival (53% and 59%) compared with patients without FOXR2 expression or MYCN-amplified tumors (80% and 88%); the poorest outcome was among those with MYCN-amplified tumors (29% and 26%). On multivariate analysis in the two data sets, FOXR2 expression was independently associated with poorer survival, with hazard ratios of 2.5 (P = .004) and 3.5 (P = .003).
Transcriptional analysis showed a high similarity between FOXR2-expressing tumors and MYCN-amplified tumors, suggesting a common mechanism of tumor initiation.
FOXR2 knockdown in FOXR2-expressing neuroblastoma cell lines resulted in cell-cycle arrest, reduced cell growth, cell death, and reduced MYCN protein levels, indicating that FOXR2 appears to be essential for development of this subgroup of neuroblastoma tumors. FOXR2 was also found to bind and stabilize MYCN protein, resulting in marked increases in MYCN protein levels in FOXR2-expressing tumors, which were sometimes comparable to levels in MYCN-amplified tumors.
The investigators concluded: “The stabilization of MYCN by FOXR2 represents an alternative mechanism to MYCN amplification to increase MYCN protein levels. As such, FOXR2 expression identifies another subset of neuroblastoma patients with unfavorable clinical outcome.”
Marcel Kool, PhD, of Hopp Children’s Cancer Center Heidelberg and German Cancer Research Center, Heidelberg, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by German Cancer Aid. For full disclosures of the study authors, visit ascopubs.org.
