Abstract 1751: Deep multi-omics analysis of uterine leiomyosarcoma reveals defective HRD signature, a novel gene fusion and the amplification of the poor-prognosis CTHRC1 gene
Authors: Falcao Raul Maia , de Souza Jorge Estefano , Mathieson William , Carlson Joseph Woodward , Petta Tirzah Braz 
Published: March 2024

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 notwell understood. To unravel the intricate molecular landscape of uLMS, we conducted a multi-omics workflow consisting of 4 high-throughput sequencing technologies; short- and long-readwhole genome sequencing (WGS), RNA-Seq, and Tandem mass tag (TMT) labeling enablingmassively parallel proteome proteomic analyses. Our study cohort consisted of 97 fresh frozentissue samples collected from 68 female patients, with 19 uLMS, 37 leiomyoma (LM), and 41normal myometrium (MM). A deep analysis of somatic variants with clinical impact revealed 46variants present in 90% of samples and two actionable therapeutic targets: IDH1_p.Arg132Cysand KRAS_p.Gly12Val. Also, 80% of the samples presented a chromothripsis signature and 60%presented the SBS3 COSMIC signature related to homologous recombination deficiency (HRD).Analysis of the proliferation score in RNA-Seq data revealed a notable difference among thetumor groups, signifying a higher proliferation index in the uLMS group, suggesting a moreaggressive growth pattern with implications for clinical behavior and disease progression. Afterapplying a customized workflow to identify balanced chromosomal abnormalities of genefusions with clinical impact, the proto-oncogene eukaryotic elongation factor 1 alpha (EEF1A1)emerged as a prominent fusion partner. Eight fusions in 7 samples were identified withtranscriptional overexpression in positive cases. At the proteomic level the enrichment analysisunveiled activated pathways associated with the innate immune system, while suppressedpathways pertained to extracellular matrix (ECM) organization and smooth muscle contraction.With an integrated bioinformatics pipeline, we identified copy number amplification of theCTHRC1 gene in 80% of the samples, accompanied by increased gene expression and proteinlevels. This gene is related to collagen remodeling and degradation and has been demonstratedto be upregulated in some solid tumors and is closely associated with malignancy. Survivalcurve analysis highlighted a significantly poorer prognosis in uLMS exhibiting CTHRC1 geneamplification with potential clinical relevance of CTHRC1 amplification as a prognostic indicatorin uLMS. Taken together these results show the overall suppression of ECM and collagenremodeling in uLMS associated with poor prognosis. Additionally, these data provide the firstevidence that the EEF1A1 gene has a strong selective pressure in uLMS underscoring theindispensable role of precision genomics in advancing precision medicine.

Citation Format: Raul Maia Falcao, Jorge Estefano de Souza, William Mathieson, Joseph Woodward Carlson, Tirzah Braz Petta. Deep multi-omics analysis of uterine leiomyosarcoma reveals defective HRD signature, a novel gene fusion and the amplification of the poor-prognosis CTHRC1 gene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1751.