Identificação de alterações no transcritoma associadas à progressão metastática em adenocarcinoma de reto
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Data
2019-01-29
Autores
Minutentag, Iael Weissberg
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Universidade Estadual Paulista (Unesp)
Resumo
Introdução: Apesar dos avanços no tratamento, cerca da metade dos pacientes com câncer de reto (CR) desenvolverá metástase à distância. No entanto, as vias biológicas envolvidas na progressão do câncer não são totalmente conhecidas. Neste estudo, investigamos os perfis moleculares e imunológicos em adenocarcinomas de reto relacionados à progressão metastática visando identificar biomarcadores moleculares e/ou alvos terapêuticos. Pacientes e Métodos: O transcritoma de 15 tecidos de CR metastático (M) e não-metastático (NM) pré-tratamento e de duas amostras de tecido de reto normais foi avaliado utilizando a plataforma Clariom D. Os genes foram considerados diferencialmente expressos quando a alteração de expressão era maior que 2 vezes e o valor de p <0,05 e detectados com o pacote limma. As funções moleculares e vias biológicas foram determinadas com a ferramenta Enricher. Os achados foram validados utilizando dados do TCGA e o perfil imunológico determinado com o algorótimo xCell. Resultados: A comparação entre os grupos M e NM revelou 52 genes diferencialmente expressos, sendo 27 regulados positivamente e 25 regulados negativamente. O gene ANLN foi detectado com o maior valor de fold change nos tumores metastáticos. Além disso, expressão aumentada de ANLN foi associada com menor sobrevida em pacientes com CR. A via do fator de crescimento endotelial vascular (VEGF) foi detectada como alterada nos tumores M. Validação dos resultados com dados do TCGA confirmou o gene ANLN como associado aos tumores do grupo M. Além disso, os genes KIF14, XRCC2 e GPX3, que possuem importantes funções na carcinogênese, também foram detectados. As populações de células imunes infiltrantes identificadas como mais significativas nos tumores M foram células dendríticas plasmocitóides (pDC), T-helper 2 (Th2) acompanhadas de diminuição das células T reguladoras (Treg), que podem desempenhar um papel na evasão imune do câncer, favorecendo a progressão da doença. Conclusões: Os perfis transcriptômico e imunológico aqui identificados revelaram potenciais marcadores moleculares e alvos para terapia que podem ser úteis para a medicina de precisão em pacientes com adenocarcinomas de reto
Introduction: Despite advances in treatment, about half of patients with rectal cancer (RC) will develop distant metastasis. However, the biological pathways underpinning the cancer progression are not fully understood. In this study, we sought to identify molecular and immunological profiles in rectal adenocarcinomas related to metastatic progression aiming to identify molecular biomarkers and/or therapeutic targets. Patients and Methods: Transcriptome analysis of 15 pre-treatment metastatic (M) and non-metastatic (NM) rectal cancer tissues and two normal rectal tissue samples was evaluated using Clariom D platform. Genes were considered differentially expressed when presenting 2-fold change and p<0.05 and were obtained with limma package . Molecular function and biological pathways with the Enricher package. Our findings were validated from the TCGA database and the immunological profile was determined using the xCell algorithm. Results: The comparison of M with NM groups revealed 52 differentially expressed genes, being 27 up-regulated and 25 down-regulated. ANLN gene was detected as the top gene upregulated in M tumours. Additionally, ANLN overexpression was associated with shorter survival in RC patients. Vascular endothelial growth factor (VEGF) pathway was detected as altered in M tumours. Cross-study validation with TCGA dataset confirmed ANLN gene as associated with M tumours. Furthermore, KIF14, XRCC2 and GPX3 genes, which have important carcinogenesis functions, were also detected. The most significant infiltrating immune cell populations in M tumours were plasmacytoid dendritic cells (pDCc), T-helper 2 (Th2) that together with diminishment of T regulatory (Treg) cells, can play a role in cancer immune evasion leading to disease progression. Conclusions: The transcriptomic and immunological profiles identified here revealed potential molecular markers and targets for therapy which can be useful for precision medicine in patients with rectal adenocarcinomas.
Introduction: Despite advances in treatment, about half of patients with rectal cancer (RC) will develop distant metastasis. However, the biological pathways underpinning the cancer progression are not fully understood. In this study, we sought to identify molecular and immunological profiles in rectal adenocarcinomas related to metastatic progression aiming to identify molecular biomarkers and/or therapeutic targets. Patients and Methods: Transcriptome analysis of 15 pre-treatment metastatic (M) and non-metastatic (NM) rectal cancer tissues and two normal rectal tissue samples was evaluated using Clariom D platform. Genes were considered differentially expressed when presenting 2-fold change and p<0.05 and were obtained with limma package . Molecular function and biological pathways with the Enricher package. Our findings were validated from the TCGA database and the immunological profile was determined using the xCell algorithm. Results: The comparison of M with NM groups revealed 52 differentially expressed genes, being 27 up-regulated and 25 down-regulated. ANLN gene was detected as the top gene upregulated in M tumours. Additionally, ANLN overexpression was associated with shorter survival in RC patients. Vascular endothelial growth factor (VEGF) pathway was detected as altered in M tumours. Cross-study validation with TCGA dataset confirmed ANLN gene as associated with M tumours. Furthermore, KIF14, XRCC2 and GPX3 genes, which have important carcinogenesis functions, were also detected. The most significant infiltrating immune cell populations in M tumours were plasmacytoid dendritic cells (pDCc), T-helper 2 (Th2) that together with diminishment of T regulatory (Treg) cells, can play a role in cancer immune evasion leading to disease progression. Conclusions: The transcriptomic and immunological profiles identified here revealed potential molecular markers and targets for therapy which can be useful for precision medicine in patients with rectal adenocarcinomas.
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Palavras-chave
Metástase, Metastasis, Adenocarcinoma de reto, Progressão tumoral, Células imunes, Rectal adenocarcinoma, Tumour progression, Immune profile