Ultra-rare sarcoma

Limited availability of tumor samples, absence of model systems, lower number of patients for understanding of disease biology and drug development are critical hurdles in advancing basic, translational, and clinical research in rare cancers (<6 cases per 100,000/year) such as sarcoma. A subset of sarcoma, termed as ultra-rare sarcoma (≤1 case per 1,000,000, Stacchiotti S et al, 2021, Cancer, 27:2934) are exceedingly rare, with significant augmentation of above challenges. Our team aims to push forward ultra-rare sarcoma research by performing in-depth molecular characterization of tumor samples to inform diagnosis, classification, identification of pathognomonic alterations, model development, and entry points for biology-guided treatment.

One example of ultra-rare sarcoma is follicular dendritic sarcoma (FDCS) that originates from follicular dendritic cells (FDCs). Diagnosis of FDCS is difficult due to histological similarities with many epithelial, mesenchymal, meningeal, or lymphoid malignancies. FDCS patients have poor prognosis and are still commonly treated with a lymphoma chemotherapy regimen (CHOP) despite evidence of mesenchymal origin of FDCs. We have assembled a cohort of >30 FDCS samples and have characterized the genomic and transcriptomic landscape of alterations, which led to identification of previously not described targetable lesions and oncogenic mechanisms, such as BRAFV600E mutations and telomerase overexpression by enhancer hijacking. Results of our analysis have led to clinical benefit to FDCS patient and we have identified a rare histological subtype of this ultra-rare sarcoma. We continue to characterize this intriguing disease using DNA methylation landscape and spatial technologies.