A Novel ACVR2A::RAF1 Fusion in Spindle Cell Sarcoma

Abstract

Background

Kinase-rearranged spindle cell sarcomas are characterized by unique molecular features. The advent of next-generation sequencing (NGS) has enabled the detection of a multitude of kinase fusions, thereby contributing to the accurate categorization of these tumors.

Case Presentation

A 37-year-old woman experienced the fourth recurrence of a cranial base tumor 25 years following the initial surgery and radiation therapy. Histological analysis disclosed spindle-shaped and oval tumor cells, along with a high number of mitotic figures. Immunohistochemistry showed a null immunophenotype, negative for pan-TRK, S-100, CD34, pan-CK, GFAP, and Olig2. Molecular analysis of the tumor tissue identified a novel ACVR2A::RAF1 fusion, comprising the first four exons of ACVR2A and the last nine exons of RAF1. The resulting fusion protein retains the extracellular and transmembrane domains of ACVR2A, while its kinase domain is replaced by the kinase domain of RAF1. This hybrid protein likely contributes to tumorigenesis by activating RAF1 signaling in response to ACVR2A ligands from the TGF-β superfamily.

Treatment and Outcome

The patient was treated with the MEK1 inhibitor Trametinib, 2 mg per time and once a day. One month later, MRI showed significant tumor shrinkage and pain relief.

Conclusion

The ACVR2A::RAF1 fusion represents a novel genomic profile in RAF1-rearranged spindle cell sarcoma, offering a rational basis for targeted therapy. This case highlights the importance of molecular diagnostics in identifying actionable targets and guiding treatment, potentially leading to significant clinical benefits.