Abstract
Based on the transcriptome analysis of 555 sarcomas, we identified a group of tightly clustered leiomyosarcomas (LMS) due to their gene expression homogeneity. We named them “hLMS” and the other LMS “oLMS”. We derived a transcriptional signature able to identify each group and used it to classify patients from two independent cohorts. In all cohorts, hLMS were preferentially carried by women, located in the internal trunk, highly differentiated, and similarly altered at the genomic level. Based on integrative bioinformatic analysis, we show that hLMS originate from vascular smooth muscle cells presenting both contractile and synthetic characteristics, while oLMS could derive from fibroblasts. We found strong MYOCD expression to be an hLMS-specific driver and show that the MYOCD/SRF axis is essential only for hLMS survival. Identification of hLMS could become standard clinical practice, leading to the development of specific effective treatments with MYOCD/SRF inhibitors.
Statement of significance Leiomyosarcomas (LMS) are currently treated as a single entity. However, we have now identified a transcriptionally, genomically and clinically homogeneous subgroup of LMS. Their oncogenesis is driven by the acquisition of high differentiation through MYOCD over-expression. This confers them sensitivity to MYOCD/SRF inhibitors, which could thus become a potential therapeutic target.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Financial support: The Instituts Thematiques Multiorganismes (ITMO) Cancer and the Claudius Regaud Institute supported this work.
Conflict of interest: The authors declare no potential conflicts of interest.