A Deep Multi-Omics Integration Approach Reveals New Molecular Features of Uterine Leiomyosarcoma

Abstract Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer representing approximately 2-5% of all uterine malignancies. The molecular heterogeneity and pathogenesis of uLMS are not well understood and translational studies with the aim of discovering the vulnerabilities of this tumor type are of high priority. We conducted an innovative comprehensive multi-omics integration study from DNA to protein using fresh frozen tumors to unravel unprecedented molecular features of uLMS. Here we present that two tumors harbor actionable therapeutic targets, IDH1ₚ. Arg132Cys and KRASₚ. Gly12Cys and homologous recombination deficiency (HRD) was the most predominant genomic signature, suggesting that uLMS patients could benefit from individualised precision medicine. Additionally, 80% of the samples presented a chromothripsis signature reinforcing the aneuploidy phenotype of these tumors. Moreover, uLMS with high proliferation score and high Ki67 expression presented a worse overall survival. By applying an innovative pipeline to explore structural variants, we observed a high frequency of balanced translocation involving the gene EEF1A1 with enrichment of EGFR pathway. For the first time, uLMS proteomics analysis shows the enrichment of pathways associated with the suppression of innate immune system and extracellular matrix (ECM) organization. Finally, our comprehensive multi-omics integration analysis identified amplification of the gene CTHRC1 a gene from the matrisome with negative impact on the overall survival. Taken together, the deep functional multi-omics approach contributes to the detection of new molecular features of uLMS and suggests that patients would benefit from precision oncology in clinical practice.