RREB1–MKL2 fusion in biphenotypic “oropharyngeal” sarcoma: New entity or part of the spectrum of biphenotypic sinonasal sarcomas?

Abstract

An increasing number of sarcomas displaying a primitive, monomorphic spindle cell phenotype have been shown to harbor recurrent gene fusions, including biphenotypic sinonasal sarcoma (SNS). Occurring in the sinonasal area of middle-aged patients, SNS is a locally aggressive tumor harboring in 90% of cases recurrent gene fusions involving the PAX3 gene, in which the chimeric transcription factor induces an aberrant dual myogenic and neural phenotype. Here, we report an unusual oropharyngeal monomorphic spindle cell sarcoma in a 53-year-old man that revealed a novel RREB1-MKL2 gene fusion by RNA sequencing with the Illumina TruSight RNA Fusion Panel. The gene fusion was validated by RT-PCR. Although the tumor location is unusual (but head and neck seated), most of the other clinical, morphologic, immunophenotypic (focal combined expression of S100 protein, SMA, desmin, and myogenin) and oncogenic data suggest that this biphenotypic "oropharyngeal" sarcoma is closely related to the biphenotypic SNS spectrum. Notably, the RREB1-MKL2 chimeric transcription factor encoded by this fusion gene produced an increase in MKL2 expression, which regulates both neural and myogenic differentiation, mimicking the crucial role of PAX3 reported in SNS oncogenesis. NGS and especially RNA sequencing may be used to identify new candidate fusion oncogenes in soft tissue tumors, which would help in updating the existing classification. In turn, this would lead to better therapeutic management of patients.

Mesenchymal tumours with RREB1–MRTFB fusion involving the mediastinum: extra‐glossal ectomesenchymal chondromyxoid tumours?

“…Although a small subset of ECT reportedly harboured the EWSR1 rearrangement, 6,13 reminiscent of up to 45% of soft tissue myoepithelioma, 14 EWSR1 ‐rearranged ECTs were associated with an unusual histology 6 . As both our tumours and that reported by Siegfried et al 8 . were identified in an axial location, it may be worth considering RREB1–MRTFB testing of midline tumours that were originally coded as soft‐tissue myoepithelioma.…”

“…The oropharyngeal tumour reported by Siegfried was interpreted as malignant, based not on follow‐up data but on histological similarity to biphenotypical sinonasal sarcoma. After receiving adjuvant chemoradiotherapy, the patient was alive with no evidence of disease 10 months after diagnosis 8 …”

“…Interestingly, shortly before the discovery of RREB1–MRTFB in ECT, Siegfried and colleagues 8 reported on a case of mesenchymal tumour with the same fusion gene located in the oropharynx of a 53‐year‐old man that exhibited no apparent tongue involvement. The tumour consisted entirely of a fascicular spindle cell proliferation immunopositive for S100 protein, SMA, desmin and myogenin.…”

“…The predicted fusion protein contains the N‐terminal C2H2‐type zinc‐finger domain from RREB1 and the C‐terminal transcriptional activation domain and leucine zipper‐like domain from MRTFB. 8 Siegfried et al 8 . demonstrated MRTFB overexpression in their oropharyngeal spindle cell tumour, and suspected that a crucial role of MRTFB in neural 16 and muscular 17,18 development may partly explain the coexpression of neural and muscular markers in their tumour.…”

RREB1-induced upregulation of the lncRNA AGAP2-AS1 regulates the proliferation and migration of pancreatic cancer partly through suppressing ANKRD1 and ANGPTL4

“…Notable, SNS is a tumor type that is prone to local invasion. In most cases, recurrent gene fusion of the PAX3 gene has emerged 31 . Besides, overexpression of RREB1 has been observed in various types of tumors 30,31 , including PC 29 .…”