Souza, Jorge Estefano de SantanaFalcão, Raul Maia2025-07-252025-07-252025-03-14FALCÃO, Raul Maia. Identificação de biomarcadores e assinaturas moleculares em leiomiossarcoma uterino por abordagem multi-ômica. Orientador: Dr. Jorge Estefano Santana de Souza. 2025. 107f. Tese (Doutorado em Bioinformática) - Instituto Metrópole Digital, Universidade Federal do Rio Grande do Norte, Natal, 2025.https://repositorio.ufrn.br/handle/123456789/64955Uterine sarcoma is a malignant tumor with aggressive clinical progression, accountingforapproximately 3–7% of all malignant uterine neoplasms. Uterine leiomyosarcoma (uLMS)isthe most common mesenchymal subtype of uterine sarcoma. The diagnosis of uLMSisoftenincidental, occurring during hysterectomy for leiomyomas (LM) - benign tumors - andconfirmed through histopathological features such as cellular atypia, mitotic index, andtumorcell necrosis. From a molecular perspective, developing effective studies toidentifydiagnostic biomarkers for uLMS is challenging due to the tumor's molecular heterogeneityand limited sample availability. In this study, we conducted a comprehensive multi-omicsintegration analysis (genomics, transcriptomics, and proteomics) using freshtumorstouncover the molecular characteristics of uLMS. The results identified twoactionabletherapeutic targets, IDH1_p.Arg132Cys and KRAS_p.Gly12Cys, in metastatic patients.Homologous recombination deficiency (HRD) was observed as the most predominantgenomic signature. Additionally, 80% of the samples exhibited a chromothripsis signature,reinforcing the aneuploid phenotype of these tumors. uLMS tumors were characterizedbyahigh proliferation score and elevated expression of the Ki67 gene (MIM:176741), whichwereassociated with worse prognosis. Furthermore, a high frequency of in-frame fusioneventsinvolving the EEF1A1 gene (MIM:130590) was reported. The multi-omics integrationanalysis identified amplification of the CTHRC1 gene (MIM:610635), which hadanegativeimpact on disease prognosis. Lastly, the PSMB9 gene (MIM:177045) was foundtobeoverexpressed with heterogeneous gene expression values in the uLMS group. Quartilegroups showed no significant differences between high and low PSMB9 expressionvaluesinterms of 3- and 5-year survival times. However, the presence of tumor-infiltratinglymphocytes (TILs) CD8+ contributed to tumor cell recognition and immune systemresponse.This presence was associated with significant differences linked to better survival outcomeswhen considering the CD8+/PSMB9 ratio in 3-year survival. These findings contributetoabetter understanding of immune response mechanisms and extracellular matrix(ECM)interactions, suggesting that uLMS patients could benefit from individualizedprecisionmedicine.pt-BRAcesso AbertoLeiomiossarcoma uterinoImunoproteasomaOncologia de precisãodoctoralThesisCIENCIAS BIOLOGICAS