Transcriptomic Subgroups in Soft Tissue Tumors Correlate with Morphologic Subtype, Genomic Features, and Outcome

Soft tissue tumors (STT) are highly heterogeneous neoplasms with more than 100 recognized subtypes, many of which lack reliable diagnostic or prognostic markers. We aimed to evaluate the clinical utility of transcriptome sequencing [RNA sequencing (RNA-seq)] in classifying STTs and identifying prognostically relevant subgroups.

We performed RNA-seq on 704 tumors representing 56 histologic subtypes, integrating global gene expression (GGE) profiles, fusion transcript detection, genomic features, and clinicopathologic data. Unsupervised clustering and machine learning approaches were used to refine tumor classification and identify prognostic transcriptomic signatures.

We identified more than 200 pathogenic gene fusion transcripts, including 40 not previously described. Strong GGE profiles were seen for many morphologic subtypes, especially for those characterized by specific gene fusions. Sarcomas with complex genomes, such as myxofibrosarcoma, undifferentiated pleomorphic sarcoma, and leiomyosarcoma (LMS), showed less distinct GGE profiles, and for LMS, subclusters correlating with genomic profiles were seen. On the basis of GGE profiles and other data, the diagnosis was changed in 5.7% of the cases. Comparison with follow-up data identified transcriptional subclusters among sarcomas with complex genomes that correlated with metastasis-free survival.

Transcriptomic profiling enhances diagnostic precision, uncovers novel oncogenic fusions, and provides prognostic information in STTs. Still, the results of the current study suggest that, due to the morphologic and clinical diversity of these tumors, multicenter collaborative studies are needed to fully explore the potential of RNA-seq in STTs.