Valor pronóstico del estudio molecular en la enfermedad de cushing
- Autores: Paloma Moreno Moreno
- Directores de la Tesis: Justo Castaño (dir. tes.), Rául Miguel Luque Huertas (dir. tes.), María Angeles Gálvez Moreno (codir. tes.)
- Lectura: En la Universidad de Córdoba (ESP) ( España ) en 2022
- Idioma: español
- Tribunal Calificador de la Tesis: Antonio Jesús Martínez Fuentes (presid.), Alfonso Calañas Continente (secret.), Cristina Álvarez Escolá (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Córdoba
- Materias:
- Enlaces
- Tesis en acceso abierto en: Helvia
- Resumen
1. Introducción o motivación de la tesis.
La enfermedad de Cushing (EC) se origina por un tumor hipofisario secretor de hormona adrenocorticotrópica (ACTH), microadenoma en el 95% de los casos. Los tumores hipofisarios secretores de ACTH representan el 14% de los adenomas hipofisarios intervenidos. La morbimortalidad de pacientes con EC no controlada es elevada, presentando una tasa de mortalidad estandarizada cinco veces superior a la de la población sana. La EC se asocia con alteraciones metabólicas, de hipercoagulabilidad, cardiovasculares, óseas, cognitivas y psicológicas y, en consecuencia, con un aumento de la mortalidad. La normalización de los niveles de cortisol conduce a una reducción significativa de la mobimortalidad. La cirugía transesfenoidal en pacientes con tumores hipofisarios secretores de ACTH presenta buenos resultados, siendo un procedimiento seguro y eficaz, pero aun así, la enfermedad persiste en alrededor del 22% de los pacientes con EC tras la cirugía. Además, en los pacientes que consiguen la remisión tras el tratamiento quirúrgico, la recidiva puede ocurrir en más de un 50% de los casos, por lo que es necesario el seguimiento de por vida de estos pacientes. La predicción de la remisión y recidiva posquirúrgica de la EC, es un desafío en la práctica clínica, y hasta el momento, no existen biomarcadores útiles para predecirlo con precisión.
Por otro lado, un tratamiento médico eficaz en pacientes en los que la cirugía no esté indicada, es necesario para conseguir el control de los síntomas, una disminución de la morbimortalidad y una mejor calidad de vida. Conocer el perfil molecular de estos tumores puede ser determinante en la elección del tratamiento más adecuado.
2. Contenido de la investigación.
Sobre la base de lo expuesto anteriormente, el objetivo principal de la presente Tesis doctoral fue determinar si el estudio de los marcadores moleculares de los ACTHomas, las características clínicas y los parámetros bioquímicos-radiológicos, de forma individual o combinada, pueden predecir la remisión o recidiva de la EC. Asimismo, y como objetivo secundario, se determinó si las características clínicas y/o los parámetros bioquímicos-radiológicos al diagnóstico de la EC, pueden predecir la expresión molecular a nivel tumoral. Para llevar a cabo el presente estudio, se diseñó y llevó a cabo un estudio observacional retrospectivo multicéntrico [6 Hospitales Universitarios: Reina Sofía de Córdoba, Virgen del Rocío de Sevilla, de la Ribera (Alzira, Valencia), Politécnico La Fe de Valencia, de Albacete, y General de Alicante], en el que se incluyeron 60 pacientes diagnosticados de EC (88,3 % mujeres), tratados quirúrgicamente, y clínicamente bien caracterizados (datos demográficos, bioquímicos, radiológicos, y patológicos), en los que se disponía de una pieza tumoral tras la cirugía en la que se realizó el estudio molecular del tumor.
En nuestro estudio, la respuesta clínica y el seguimiento a largo plazo en pacientes con EC se evaluaron por remisión después de la cirugía y la presencia de recidiva durante el seguimiento. La remisión se definió como la normalización del cortisol libre en orina de 24 horas (CLU 24 h), el cortisol salival nocturno (CS) y el cortisol tras 1 mg de dexametasona (DXT) en aquellos pacientes que no presentaron insuficiencia suprarrenal después de la cirugía. La insuficiencia suprarrenal se definió como cortisol basal menor de 5 µg/dL, realizado inmediatamente después de la cirugía y al mes después de la cirugía. La recidiva de EC se definió como la reaparición de las características clínicas y bioquímicas del hipercortisolismo después de la remisión inicial: niveles elevados de CLU 24h (1,6 veces el nivel superior de la normalidad) y/o niveles superiores de CS (puntos de corte: 0,27 µg/dL) y/o falta de inhibición del cortisol plasmático después de 1 mg de dexametasona (DXT) (punto de corte: > 1,8 µg/dL). Se analizaron los niveles de cortisol tras 1 mg de DXT al mes de la cirugía en todos los pacientes que no presentaron hipocortisolismo tras la cirugía. Los pacientes fueron tratados de acuerdo con las guías clínicas disponibles. Se realizó cirugía transesfenoideal en todos los pacientes y se obtuvo la muestra tumoral tras ser procesada por los anatomopatólogos de cada hospital. Cada una de estas muestras fue procesada y conservada hasta la realización del estudio molecular en el Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC).
El periodo de seguimiento en este estudio fue de 24 - 152 meses tras la cirugía. La edad media al diagnóstico de la EC fue de 40 años (15-78). La mayoría de los casos presentaban al diagnóstico obesidad central, plétora facial, cara de luna llena, astenia y labilidad emocional (más del 80 %). También fue frecuente el hirsutismo y la atrofia muscular (79,4 y 78,8 % respectivamente). La comorbilidad más prevalente fue la hipertensión arterial (50 %). En el estudio de imagen, 34 pacientes (56,7 %) presentaban microadenomas [mediana ± RI: macroadenomas (17 ± 8,5 mm), microadenomas (6 ± 1,6 mm)]. En la pieza tumoral se analizó el perfil de expresión de los genes de los distinto subtipos de receptores de somatostatina (SSTs) que reveló que el receptor de somatostatina subtipo 5 (SST5) era el subtipo de receptor dominante expresado en muestras de ACTHoma, seguido de receptor de somatostatina subtipo 1 (SST1) >> receptor de somatostatina subtipo 2 (SST2) > receptor de somatostatina subtipo 3 (SST3) > variante truncada del receptor de somatostatina subtipo 5-TMD5 (SST5TMD5) > variante truncada del receptor de somatostatina subtipo 5-TMD4 (SST5TMD4). También se analizó el perfil de receptores de dopamina (DR) y se encontró que el receptor más expresado era el receptor de dopamina subtipo 2 (DRD2), seguido del receptor de dopamina subtipo 4 (DRD4) >> receptor de dopamina subtipo 5 (DRD5) > receptor de dopamina subtipo 1 (DRD1). En el caso del sistema ghrelina, los componentes dominantes de este sistema fueron el receptor truncado de ghrelina (GHRS1b) ≥ receptor de GH tipo 1a (GHSR1a), seguidos de la enzima Ghrelina-O-acil-transferasa (GOAT) ≥ variante In1-ghrelina > ghrelina nativa. Se observó que el precursor de la ACTH (POMC), la variante del receptor de vasopresina-1b (AVPR1b) y el receptor de hormona liberadora de corticotropina (CRHR1) se expresaban considerablemente en las muestras de ACTHoma. También encontramos entre los marcadores de proliferación, que los niveles de expresión del gen transformador de tumor hipofisario (PTTG1) eran significativamente más altos que los niveles del antígeno KI-67 (MKI67). Además, los resultados de nuestro estudio mostraron que algunas variables clínicas de la EC se correlacionaban significativamente con variables bioquímicas y moleculares. El hallazgo más relevante fue descubrir que algunos parámetros clínicos/bioquímicos y componentes moleculares se asociaban claramente con la remisión de la EC después de la primera cirugía (ej. menor tamaño del tumor y las determinaciones posquirúrgicas de cortisol basal, CLU 24h, cortisol tras 1 mg DXT y prolactina, menor expresión de SST1, mayor expresión de CRHR1 y MKI67, etc.), y que la combinación de algunos de estos parámetros clínicos y moleculares podía predecir con gran precisión la remisión de la EC después de la primera cirugía.
3. Conclusión.
Las principales conclusiones alcanzadas en esta Tesis son: • Existen marcadores moleculares de los ACTHomas, concretamente SST1 y CRHR1, que pueden predecir la remisión de la EC en pacientes tratados con cirugía.
• Existen parámetros clínicos, concretamente el tamaño del tumor y las determinaciones posquirúrgicas de cortisol basal, CLU 24h, cortisol tras 1 mg DXT y prolactina (PRL), que pueden predecir la remisión de la EC en pacientes tratados con cirugía.
• El análisis combinado de dos marcadores moleculares de los ACTHomas (SST1 y CRHR1) y dos parámetros clínicos (tamaño del tumor y el cortisol basal posquirúrgico) puede predecir con gran precisión la evolución clínica y la remisión de pacientes con EC tratados con cirugía.
• Existe una correlación entre las características clínicas y/o los parámetros bioquímicos-radiológicos al diagnóstico de la EC que pueden predecir la expresión molecular a nivel tumoral. Concretamente, el cortisol basal al diagnóstico se correlaciona inversamente con la expresión de SST1, SST2, SST3, DRD1, DRD2T, DRD2L y DRD5, y el nivel de ACTH al diagnóstico se correlaciona inversamente con la expresión de SST1, SST2, SST3, DRD1, DRD2T, DRD2L, DRD4, DRD5 y GHSR1a.
Por tanto, los resultados de esta Tesis Doctoral aportan una conclusión clínicamente relevante puesto que demuestran por primera vez que el análisis combinado de un conjunto concreto de biomarcadores clínicos y moleculares en la pieza tumoral de pacientes con ACTHomas es capaz de predecir con gran precisión la evolución clínica y la remisión de los pacientes. Por tanto, el perfil molecular posquirúrgico representa una valiosa herramienta para la evaluación clínica y el seguimiento de los pacientes con EC.
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