FXR1 expression profiles in pediatric rhabdomyosarcoma

Introduction
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and arises from abnormal muscle development. We reported previously that Fragile-X-Related 1 (FXR1) gene, essential to normal myogenesis, was highly expressed in RMS relative to other embryonal tumors. This current study explored the association of FXR1 expression with RMS patient characteristics and treatment response.

Methods
Our institutional cancer registry identified RMS patients ≤18 years treated between 1980-2019 (n=152). Patients were categorized according to tumor histology (embryonal or alveolar), PAX/FOXO1 translocation, and vital status. Immunohistochemistry characterized FXR1 protein expression in current treatment era specimens sampled before (n=46) and after (n=35) chemotherapy. For generalizability, demographic data of RMS patients ≤18 years from the statewide cancer registry were analyzed (n=104; 2004-16). Kaplan-Meier and Cox regression models examined the association of FXR1 expression with relapse-free (RFS) and overall survival (OS).

Results (Table)
FXR1 was most intensely expressed in the perinuclear cytosol of undifferentiated rhabdomyoblasts. FXR1 expression was ubiquitous and strong at diagnosis and therefore did not associate with OS. However, higher FXR1 expression at diagnosis associated with worse RFS in translocation-positive patients (p= 0.0411). Among embryonal and translocation-negative RMS, survivors showed a significantly greater decrease in FXR1 expression after chemotherapy (p<0.001) compared to decedents (p=0.8). In contrast, alveolar and translocation-positive RMS specimens showed insignificant change in FXR1 expression before and after therapy. Sex, race, and income were not significantly associated with survival, whereas histology, translocation status, stage, and clinical group were. Patient demographics and clinical characteristics were consistent between patients treated at our institution and across the state.

Conclusions
FXR1 was expressed strongly across RMS specimens regardless of disease or patient characteristics, and particularly in undifferentiated cells. Decreased FXR1 expression after chemotherapy associated with improved survival for embryonal and translocation-negative RMS patients, suggesting a biomarker for better treatment response.