Novel Gene Fusions in Rhabdomyosarcoma

Abstract

Abstract Introduction/Objective Rhabdomyosarcoma (RMS) encompasses a heterogeneous group of tumors with striated muscle morphology and/or immunophenotype. Molecular analysis of rhabdomyosarcoma has identified a number of aberrations useful for classification. Initially, fusion associated RMS was restricted to tumors with FOXO1 rearrangements, confirming the diagnosis of alveolar RMS, and identifying patients with poor-outcome. Spindle cell RMS, have been described with VGLL2 fusions, EWSR1/FUS-TFCP2 rearrangements, and myoD1 mutations. In addition, NCOA2-MEIS1 fusion gene was recently described in two primary intraosseous RMSs sharing primitive histology. Herein we report two cases of spindle cell RMS, harboring different novel fusion genes, one presenting EP300-VGLL3, and the second with NCOA2-MEIS1 and CAV1-MET. Methods Two cases of RMS were retrieved from the pathology files at the University of Miami Hospital (UMH) and Jackson Memorial Hospital (JMH). Morphology and immunohistochemistry were reviewed. A commercial genomic profiling test for both cases was also analyzed. The study was approved by the Institutional Review Board at UMH. Results Case #1 is a 36-year-old man presented with a 1.5 cm submucosal mass in the ventral left tongue. The biopsy revealed a malignant spindle cell neoplasm and immunohistochemistry showed tumor cells positive for desmin, SMA, myogenin and MYOD-1. A partial glossectomy was performed, achieving negative resection margins. Next- generation sequencing (NGS) identified an EP300-VGLL3 fusion. The patient is currently being followed and has been disease-free for 6 months. Case #2 is a 19-years-old male with no medical history admitted with lower extremities weakness and a large expansile pelvic bone lesion and multiple spinal metastases. Biopsy from the pelvic lesion revealed malignant primitive round cells and short spindle cells arranged in fascicles which were positive for desmin, MYOD-1, TLE-1 and CD99 and focally positive for myogenin and WT-1. NGS identified two fusion genes, NCOA2- MEIS1 and CAV1-MET. Conclusion Different types of rhabdomyosarcoma are associated with a variety of different gene fusions and some may be of prognostic significance. Our two cases are the first reported with EP300-VGLL3 and CAV1-MET fusion genes. CAV1-MET oncogenic potential has been described only in lung cancer. The prognostic significance of rhabdomyosarcoma with novel gene fusions requires longer follow-up and the identification of additional cases.