Oncogenic Gene-Expression Programs in Leiomyosarcoma and Characterization of Conventional, Inflammatory, and Uterogenic Subtypes

Abstract

◥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 with diverse sarcomas, nonmesenchymal 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, including IGF1R and genes involved in 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 expresses a unique subset of genes that may be useful in the management of LMS: IGF1R was enriched in conventional LMS, worse disease-specific survival was observed in inflammatory LMS, and prolactin was elaborated by uterogenic LMS. These results extend our understanding of LMS biology and identify several strategies and challenges for further translational investigation.Implications: LMS has a recurrent oncogenic transcriptional program and consists of molecular subtypes with biological and possible clinical implications.

Distinct cellular origins and differentiation process account for distinct oncogenic and clinical behaviors of leiomyosarcomas

“…Several authors have already identified two or three subtypes of LMS consistently with one group harboring strong smooth muscle differentiation and a homogeneous transcriptomic profile that are similar to hLMS (8)(9)(10)(11)(12)(13)(14)(15)(16). However, our study differs from the others.…”

“…Several authors have already identified two or three subtypes of LMS consistently with one group harboring strong smooth muscle differentiation and a homogeneous transcriptomic profile that are similar to hLMS (Baird et al, 2005;Beck et al, 2010;Gibault et al, 2011a;Guo et al, 2015;Hemming et al, 2020;Italiano et al, 2013;Lee et al, 2016;Nielsen et al, 2002;Perot et al, 2009). However, our study differs from the others.…”

“…However, our study differs from the others. First, we analyzed primary tumors and excluded uterine LMS, unlike most of the other authors (Baird et al, 2005;Beck et al, 2010;Guo et al, 2015;Hemming et al, 2020). Second, we report reproducible clinical descriptions of hLMS and oLMS.…”

“…Subgroups of LMS have been identified by using different transcriptomic sequencing methods and sample collections (Baird et al, 2005;Beck et al, 2010;Gibault et al, 2011a;Guo et al, 2015;Hemming et al, 2020;Italiano et al, 2013;Lee et al, 2016;Nielsen et al, 2002;Perot et al, 2009). One subgroup was consistently highlighted with a homogeneous transcriptomic profile, expression of smooth muscle cell (SMC) differentiation markers, a higher differentiation and localized in the retroperitoneum.…”

“…Subgroups of LMS have been identified by using different transcriptomic sequencing methods and sample collections (8)(9)(10)(11)(12)(13)(14)(15)(16). One subgroup was consistently highlighted with a homogeneous transcriptomic profile, expression of smooth muscle cell (SMC) differentiation markers, a higher differentiation and localized in the retroperitoneum.…”