Perinucleolar Compartment (PNC) Prevalence as an Independent Prognostic Factor in Pediatric Ewing Sarcoma: A Multi-Institutional Study

SIMPLE SUMMARY: The perinucleolar compartment (PNC) plays an important role in tumorigenesis. Its presence has been correlated with poor prognosis and cancer metastasis. Ewing sarcoma (EWS) is the second most common bone cancer in children and young adults. Currently, there are no clinically relevant markers predictive of which patients with Ewing sarcoma will experience early relapse, and there are no effective targeted agents for this disease to date. Using samples from primary and metastatic tumors, immunohistochemical study of PNC demonstrates a higher PNC prevalence in metastatic sites compared to primary tumors, and that a high prevalence of PNC was correlated with a distinct microRNA profile and shorter disease-free survival, highlighting its utility as a clinically relevant predictive biomarker associated with tumor metastasis. PNC prevalence was higher in Hispanic patients, potentially demonstrating a biologic basis for the ethnic disparity in this tumor. ABSTRACT: The perinucleolar compartment (PNC) is a small nuclear body that plays important role in tumorigenesis. PNC prevalence correlates with poor prognosis and cancer metastasis. Its expression in pediatric Ewing sarcoma (EWS) has not previously been documented. In this study, we analyzed 40 EWS tumor cases from Caucasian and Hispanic patients for PNC prevalence by immunohistochemical detection of polypyrimidine tract binding protein and correlated the prevalence with dysregulated microRNA profiles. EWS cases showed staining ranging from 0 to 100%, which were categorized as diffuse (≥77%, n = 9, high PNC) or not diffuse (<77%, n = 31) for low PNC. High PNC prevalence was significantly higher in Hispanic patients from the US (n = 6, p = 0.017) and in patients who relapsed with metastatic disease (n = 4; p = 0.011). High PNC was associated with significantly shorter disease-free survival and early recurrence compared to those with low PNC. Using NanoString digital profiling, high PNC tumors revealed upregulation of eight and downregulation of 18 microRNAs. Of these, miR-320d and miR-29c-3p had the most significant differential expression in tumors with high PNC. In conclusion, this is the first study that demonstrates the presence of PNC in EWS, reflecting its utility as a predictive biomarker associated with tumor metastasis, specific microRNA profile, Hispanic ethnic origin, and poor prognosis.