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Ministerio de Universidades - Gobierno de España

Título: MOLECULAR DIAGNOSIS OF UTERINE LEIOMYOMA BY NEXT GENERATION SEQUENCING
Autor: Machado López, Alba
Universidad: Universitat de València (Estudi General)
Departamento: Bioquímica y biología molecular
Fecha de Lectura: 23/01/2024
Mención Europeo / Mención Internacional: Concedido
Programa de doctorado: Programa de Doctorado en Biomedicina y Biotecnología por la Universitat de València (Estudi General)
Dirección:
- Simón Vallés, Carlos (DIRECTOR)
- MAS PERUCHO, AYMARA (CODIRECTOR)
- Valbuena Perilla, Diana (CODIRECTOR)
Tribunal:
- GILABERT ESTELLES, JUAN (PRESIDENTE)
- Altmäe, Signe (SECRETARIO)
- Tinelli, Andrea (VOCAL)
Descriptores:
- SECTOR DE LA SALUD
Localización: BIBLIOTECA DE CIENCIAS

751617_1659086.pdf

Marcador: https://www.educacion.gob.es/teseo/mostrarRef.do?ref=2488629Añadir a favoritos.
Resumen:
Uterine leiomyoma (LM) is the most frequent benign uterine tumor, with an incidence of up to 70% in women of reproductive age. Around 30% of patients will suffer symptoms such as abnormal uterine bleeding, pelvic pain and infertility. Molecular analysis of LM has identified driver mutations in MED12, HMGA2, FH and COL4A5/COL4A6, as well as extensive cellular heterogeneity. Unfortunately, the specific tumorigenic processes that cause LM remain elusive, leading to challenges in their clinical management. To address these challenges, the aim of this work is to investigate the molecular and cellular mechanisms of LM tumorigenesis through NGS approaches. With this purpose, bulk genomic and transcriptomic analyses were performed on 38 women undergoing surgery for the treatment of LM, by collecting tumor tissue and >3 cm distant matched myometrium (MM). Whole exome sequencing enabled the detection of 42887 somatic SNVs, 3 mutational signatures and 2033 somatic CNVs in LM. RNAseq revealed 219 differentially expressed genes and fusion transcripts disrupting genes such as RAD51B and HMGA2 in LM. Additionally, 8 patients were subjected to single-cell transcriptomics (scRNAseq), spatial transcriptomics and single-cell proteomics (scProt). scRNAseq showed no differences in cell composition between LM and MM. However, we found clear differences in the transcriptomic profile of all cell populations, with a set of genes associated with RhoGTPAse signaling and cell stress dysregulated in all of them. Further, SMC/fibroblasts showed dysregulation of ECM production, while in endothelial and perivascular cells there was an altered response to oxidative stress and impaired angiogenesis in LM. Cell to cell communication analysis revealed impaired signaling in LM associated with angiogenesis, fibrosis, and proliferation, affecting several pathways, some completely absent (PERIOSTIN, CSPG4, CXCL, NRG) and some only present (ncWNT, IL6, PROS) in LM. We have also defined a differentiation trajectory from canonical fibroblasts towards canonical SMCs. This trajectory was disrupted in LM, which overexpressed several genes of the transitional phase (EGFR, ITGA11, MICAL2, MICAL3). Spatial transcriptomic analysis showed a shift from SMC to fibroblasts in LM, suggesting a profibrotic pattern. scProt profiling identified an additional stem-like population, which overexpressed genes involved in replication, transcription and translation in LM (DUT, RPL17, RBM14). Notably, CALU and RAB2A showed alterations at all molecular levels, suggesting their potential relevance in the development of LM. Altogether, our data demonstrates the complex interplay between molecular and cellular features that underlie LM tumorigenesis and suggests novel tumorigenic markers. These findings may contribute to the basic knowledge essential for developing innovative diagnostic and therapeutic approaches, that ultimately reduce the burden of LM on the health and quality of life of affected patients.

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