Oncogenic gene expression programs in leiomyosarcoma and characterization of conventional, inflammatory and uterogenic subtypes

Leiomyosarcoma (LMS) is a mesenchymal neoplasm with complex copy number alterations and characteristic loss of tumor suppressor genes without known recurrent activating mutations. Clinical management of advanced LMS relies on chemotherapy and complementary palliative approaches, and research efforts to date have had limited success identifying clinically actionable biomarkers or targeted therapeutic vulnerabilities. To explore the biological underpinning of LMS, we evaluated gene expression patterns of this disease in comparison to diverse sarcomas, non-mesenchymal neoplasms and normal myogenic tissues. We identified a recurrent gene expression program in LMS, with evidence of oncogenic evolution of an underlying smooth muscle lineage-derived program characterized by activation of E2F1 and downstream effectors. Recurrently amplified or highly expressed genes in LMS were identified that may represent therapeutic vulnerabilities, including targeting of IGF1R and retinoid signaling pathways. Though the majority of expressed transcripts were conserved across LMS samples, three separate subtypes were identified that were enriched for muscle-associated transcripts (conventional-LMS), immune markers (inflammatory-LMS) or a uterine-like gene expression program (uterogenic-LMS). Each of these subtypes express a unique subset of genes that may be useful in the managemeny of LMS: IGF1R was enriched in conventional LMS with prognostic implications, worse disease-specific survival was observed in inflammatory LMS, and prolactin was elaborated by uterogenic LMS and may represent a disease biomarker. These results extend our understanding of LMS biology and identify several strategies and challenges for further translational investigation. RNA-seq from leiomyosarcoma tumors and cell line