Publication: Análisis del perfil de expresión de micrornas en neoplasias neuroendocrinas de origen gastroenteropancreático y pulmonar
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2021-07-09
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Unievrsidad Complutense de Madrid
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Abstract
Las neoplasias neuroendocrinas (NNEs) son una familia de tumores de una gran heterogeneidad biológica. Globalmente son neoplasias con un índice mutacional bajo y no se han identificado mutaciones genéticas conductoras o driver sobre las que se pueda actuar desde el punto de vista terapéutico. Sin embargo, los mecanismos epigenéticos juegan un papel determinante en la biología e historia natural de estos tumores. La expresión de los miRNAs está desregulada en cáncer a través de distintos mecanismos, incluidos la amplificación o delección de los genes que los codifican, alteraciones en la regulación de su transcripción, modificaciones epigenéticas y alteraciones en la maquinaria de su biogénesis, y pueden funcionar como oncogenes o como genes supresores de tumores dependiendo de los genes diana sobre los que actúen. Múltiples estudios han demostrado su utilidad como biomarcadores diagnósticos, pronósticos y terapéuticos en otras neoplasias, pero la evidencia en NNEs es escasa.
La hipótesis que fundamenta este trabajo es que las NNEs presentan un perfil de expresión de miRNAs característico y que la identificación de estos miRNAs desregulados puede tener una utilidad clínica diagnóstica, pronóstica, y potencialmente terapéutica. En base a ello, el objetivo global fue caracterizar el perfil de expresión de miRNAs en NNEs de origen GEP y pulmonar, y evaluar su utilidad como potenciales biomarcadores en la clínica. Con este fin hemos analizado retrospectivamente en una cohorte de 128 pacientes con NNEs la expresión de un panel de 84 miRNAs relacionados con cáncer mediante PCR-arrays en muestras pareadas tumorales y no tumorales, con los siguientes objetivos específicos: 1) identificar el perfil de expresión diferencial de miRNAs en tejido tumoral respecto al tejido sano; 2) identificar el perfil de expresión de miRNAs en función de distintas variables clínicas y patológicas de interés, 3) evaluar su valor pronóstico añadido respecto a las variables pronósticas clínicas ya conocidas, y 4) explorar los genes regulados por estos miRNAs con el fin de identificar las rutas moleculares implicadas y su relación con los hallmarks o rasgos distintivos de cáncer, identificar potenciales nuevas dianas terapéuticas y sentar las bases para estudios funcionales futuros...
Neuroendocrine neoplasms (NENs) are a family of tumors of great biological heterogeneity. Overall, they are neoplasms with a low mutational burden and no driver mutations have been identified that may be adequate targets for therapy. However, epigenetic mechanisms play a determining role in the biology and natural history of these tumors. The expression of miRNAs is deregulated in cancer through different mechanisms, including the amplification or deletion of the genes that encode them, alterations in the regulation of their transcription, epigenetic modifications and alterations in the machinery of their biogenesis. MiRNAs may function as oncogenes or as tumor suppressor genes depending on the target genes they regulate. Multiple studies have demonstrated their utility as diagnostic, prognostic, and therapeutic biomarkers in other malignancies, but the evidence in NENs is scarce. The hypothesis underlying this work is that NENs present a characteristic miRNA expression profile and that the identification of these deregulated miRNAs can be of potential diagnostic, prognostic or therapeutic utility. Based on this, the overall objective of this study was to characterize the expression profile of miRNAs in NENs of gastroentero-pancreatic (GEP) and pulmonary origin, and to evaluate their utility as potential biomarkers in the clinic. To this end, we have retrospectively analyzed in a cohort of 128 NENs patients the expression of a panel of 84 cancer-related miRNAs using PCR-arrays in paired tumor and non-tumor samples, with the following specific objectives: 1) to identify the differential miRNAs expression profile in tumor versus non-tumor tissue; 2) to identify the differential miRNA expression profile based on different clinical and pathological variables of interest, 3) to evaluate their added prognostic value with respect to the already known clinical prognostic variables, and 4) to explore the genes regulated by these miRNAs in order to identify the molecular pathways involved and their relationship to the hallmarks of cancer, identify potential new therapeutic targets, and pave the way for future functional studies...
Neuroendocrine neoplasms (NENs) are a family of tumors of great biological heterogeneity. Overall, they are neoplasms with a low mutational burden and no driver mutations have been identified that may be adequate targets for therapy. However, epigenetic mechanisms play a determining role in the biology and natural history of these tumors. The expression of miRNAs is deregulated in cancer through different mechanisms, including the amplification or deletion of the genes that encode them, alterations in the regulation of their transcription, epigenetic modifications and alterations in the machinery of their biogenesis. MiRNAs may function as oncogenes or as tumor suppressor genes depending on the target genes they regulate. Multiple studies have demonstrated their utility as diagnostic, prognostic, and therapeutic biomarkers in other malignancies, but the evidence in NENs is scarce. The hypothesis underlying this work is that NENs present a characteristic miRNA expression profile and that the identification of these deregulated miRNAs can be of potential diagnostic, prognostic or therapeutic utility. Based on this, the overall objective of this study was to characterize the expression profile of miRNAs in NENs of gastroentero-pancreatic (GEP) and pulmonary origin, and to evaluate their utility as potential biomarkers in the clinic. To this end, we have retrospectively analyzed in a cohort of 128 NENs patients the expression of a panel of 84 cancer-related miRNAs using PCR-arrays in paired tumor and non-tumor samples, with the following specific objectives: 1) to identify the differential miRNAs expression profile in tumor versus non-tumor tissue; 2) to identify the differential miRNA expression profile based on different clinical and pathological variables of interest, 3) to evaluate their added prognostic value with respect to the already known clinical prognostic variables, and 4) to explore the genes regulated by these miRNAs in order to identify the molecular pathways involved and their relationship to the hallmarks of cancer, identify potential new therapeutic targets, and pave the way for future functional studies...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 17/12/2020