Aspectos clínico-moleculares e imunológicos da Nectina-4 e Trop2 no câncer de bexiga músculo-invasivo
Data
2024-10-25
Autores
Wilson Junior, Jorge Luis 
Orientadores
Azevedo, Hatylas Felype
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: Cerca de 30% dos carcinomas uroteliais de bexiga são músculoinvasivos em sua manifestação inicial. Para os casos metastáticos, a imunoterapia com anticorpos monoclonais tem emergido como nova opção de tratamento, e dentre eles os novos Conjugados AnticorpoDroga (ADCs). Dois marcadores tem se destacado como alvos de ADCs, Nectina4 e Trop2, sendo o Enfortumab Vedotin e o Sacituzumabe Govitecan os respectivos ADCs para esses alvos . Objetivo: Analisar a expressão de Nectina4 e Trop2 em pacientes com câncer de bexiga músculoinvasivo (MIBC), e sua relação com parâmetros clínicopatológicos, moleculares e imunológicos. Casuística e Método: Foi utilizado o banco de dados de tecidos tumorais de pacientes com MIBC do projeto TCGA; para comparação com tecidos normais, foram utilizados dados do projeto GTEx. A extração dos dados foi realizada em diferentes plataformas derivadas desses projetos: a avaliação de expressão de Nectina4 e Trop2 e sua correlação com desfechos oncológicos pela plataforma GEPIA2; análise de genes coexpressos, vias funcionais e ontologia pela plataforma ENRICHR; associação com características clínicopatológicas através da plataforma UALCAN; por fim, a correlação com a imunidade linfocitária peritumoral pela plataforma TISIDB. Resultados: A Nectina4 foi superexpressa nos tecidos tumorais, comparado ao tecido normal, enquanto para Trop2 a expressão no tecido tumoral e normal foi semelhante; não houve correlação entre os níveis de expressão alto ou baixo de ambos os genes com desfechos oncológicos. A análise funcional dos genes similares à Trop2 revelou vias funcionais relacionadas a mecanismos de junções e adesão celular; a mesma avaliação em Nectina4 não mostrou vias funcionais estatisticamente significativas. Quanto aos dados moleculares e clínicopatológicos relacionados à expressão de Trop2, o estágio tumoral mostrou maior expressão nos estágios mais avançados, e maior expressão na raça asiática. A análise dos subtipos moleculares mostrou baixa expressão no subtipo neuronal. Para Nectina4, destacase a maior expressão em homens comparado às mulheres, maior expressão nos subtipos moleculares dos grupos luminais, e expressão reduzida nos subtipos neuronal e basal. Em relação ao infiltrado linfocitário peritumoral, a expressão de Trop2 foi correlacionada a menores níveis de célula T “Natural killer”, célula T CD4 ativado, e célula T helper tipo 2, enquanto Nectina4 foi correlacionada a menores níveis de linfócitos T regulador, célula T “Natural killer” e o Linfócito T Gama Delta. Conclusão: A expressão gênica no carcinoma urotelial de bexiga músculoinvasivo mostrouse aumentada para Nectina4, porém não para Trop2. Não houve diferença dos desfechos oncológicos correlacionados aos níveis de expressão para ambos os genes. Em relação a Trop2, houve maior expressão em tumores mais avançados, na etnia asiática e nos tumores papilares, e menor expressão no subtipo molecular neuronal. Já para Nectina4, houve maior expressão em homens, nos tecidos tumorais de quaisquer perfis de tabagistas e nos subtipos luminais, com menor expressão nos subtipos neuronal e basal. A imunidade linfocitária peritumoral relacionada à expressão de Trop2 e Nectina4 revelou redução de subtipos de linfócitos implicados no mecanismo de imunidade celular e humoral contra células tumorais.
Introduction: Nearly 30% of bladder urothelial carcinomas are muscleinvasive in their initial manifestation. For metastatic cases, immunotherapy with monoclonal antibodies has emerged as a new treatment option, in particular novel AntibodyDrug Conjugates (ADCs). Two epithelial proteins have emerged as targets of ADCs, Nectin4 and Trop2, with Enfortumab Vedotin and Sacituzumab Govitecan being the respective ADCs for these targets. Objective: to analyze the expression of Nectin4 and Trop2 in patients with muscleinvasive bladder cancer (MIBC), and their relationship with clinicalpathological, molecular and immunological parameters. Method: We evaluated a database of tumor tissues from patients with MIBC from the TCGA project as well as normal bladder tissues from the GTEx project for comparative purposes. Data extraction was performed on the different platforms from these projects and the correlation of Nectin4 and Trop2 expression with oncological outcomes was carried our using the GEPIA2 software. We also analyzed coexpressed genes, functional pathways and ontology using the ENRICHR platform, and the association with clinicopathological characteristics and peritumoral lymphocytic immunity was analyzed using the UALCAN and TISIDB platforms, respectively. Results: Nectin4 was overexpressed in tumors compared to normal tissues, while the expression of Trop2 was similar between tumor and normal tissues; there was no correlation between high or low expression levels of both genes with oncological outcomes. Functional analysis of genes coexpressed with Trop2 revealed functional pathways related to cell adhesion mechanisms, whereas no statistically significant functional pathways were identified for Nectin4 coexpressed genes. The analysis of the molecular and clinicopathological data revealed that Trop2 is more expressed in tumors with more advanced stages, as well as in tumors from Asian patients. For Nectin4, there was a higher expression in tumor types from men than women, as well as in the luminal subtypes, and a reduced expression was seen in the neuronal and basal subtypes. The analysis of the correlation between genes expressed in peritumoral lymphocytic infiltrates and the target genes disclosed a correlation between Trop2 expression and lower levels of natural killer T cells, activated CD4 T cells, and type 2 helper T cells, while for Nectin4 there was a correlation between its expression and lower levels of genes from regulatory T lymphocytes, natural killer T cells, and gamma delta T lymphocytes. Conclusion: We observed a higher gene expression in muscleinvasive urothelial carcinoma for Nectin4 but not for Trop2. There was no difference in oncological outcomes correlated with the expression levels for both genes. Regarding Trop2, there was a higher expression in more advanced tumor stages, in Asians, and in papillary tumors, and lower expression in the neuronal molecular subtype. For Nectin4, there was a greater expression in men, in tumor tissues of any smoking profile, and in luminal subtypes, with lower expression in neuronal and basal subtypes. Peritumoral lymphocyte immunity related to the expression of Trop2 and Nectin4 revealed a reduction in several lymphocyte subtypes involved in the mechanism of cellular and humoral immunity against tumor cells.
Introduction: Nearly 30% of bladder urothelial carcinomas are muscleinvasive in their initial manifestation. For metastatic cases, immunotherapy with monoclonal antibodies has emerged as a new treatment option, in particular novel AntibodyDrug Conjugates (ADCs). Two epithelial proteins have emerged as targets of ADCs, Nectin4 and Trop2, with Enfortumab Vedotin and Sacituzumab Govitecan being the respective ADCs for these targets. Objective: to analyze the expression of Nectin4 and Trop2 in patients with muscleinvasive bladder cancer (MIBC), and their relationship with clinicalpathological, molecular and immunological parameters. Method: We evaluated a database of tumor tissues from patients with MIBC from the TCGA project as well as normal bladder tissues from the GTEx project for comparative purposes. Data extraction was performed on the different platforms from these projects and the correlation of Nectin4 and Trop2 expression with oncological outcomes was carried our using the GEPIA2 software. We also analyzed coexpressed genes, functional pathways and ontology using the ENRICHR platform, and the association with clinicopathological characteristics and peritumoral lymphocytic immunity was analyzed using the UALCAN and TISIDB platforms, respectively. Results: Nectin4 was overexpressed in tumors compared to normal tissues, while the expression of Trop2 was similar between tumor and normal tissues; there was no correlation between high or low expression levels of both genes with oncological outcomes. Functional analysis of genes coexpressed with Trop2 revealed functional pathways related to cell adhesion mechanisms, whereas no statistically significant functional pathways were identified for Nectin4 coexpressed genes. The analysis of the molecular and clinicopathological data revealed that Trop2 is more expressed in tumors with more advanced stages, as well as in tumors from Asian patients. For Nectin4, there was a higher expression in tumor types from men than women, as well as in the luminal subtypes, and a reduced expression was seen in the neuronal and basal subtypes. The analysis of the correlation between genes expressed in peritumoral lymphocytic infiltrates and the target genes disclosed a correlation between Trop2 expression and lower levels of natural killer T cells, activated CD4 T cells, and type 2 helper T cells, while for Nectin4 there was a correlation between its expression and lower levels of genes from regulatory T lymphocytes, natural killer T cells, and gamma delta T lymphocytes. Conclusion: We observed a higher gene expression in muscleinvasive urothelial carcinoma for Nectin4 but not for Trop2. There was no difference in oncological outcomes correlated with the expression levels for both genes. Regarding Trop2, there was a higher expression in more advanced tumor stages, in Asians, and in papillary tumors, and lower expression in the neuronal molecular subtype. For Nectin4, there was a greater expression in men, in tumor tissues of any smoking profile, and in luminal subtypes, with lower expression in neuronal and basal subtypes. Peritumoral lymphocyte immunity related to the expression of Trop2 and Nectin4 revealed a reduction in several lymphocyte subtypes involved in the mechanism of cellular and humoral immunity against tumor cells.
Descrição
Citação
WILSON JUNIOR, Jorge Luís. Aspectos clínicomoleculares e imunológicos da Nectina4 e Trop2 no câncer de bexiga músculoinvasivo. 2024. 69 f. Tese (Doutorado em Urologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2024.