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La activación de la mutación del punto de acceso L205R en PRKACA y el síndrome de Cushing suprarrenal

Yanan Cao¹, Minghui He², Zhibo Gao²

¹Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.

Science (New York, N.Y.)

|April 5, 2014

Resumen

Las mutaciones genéticas en los tumores suprarrenales causan el síndrome de Cushing. Los investigadores encontraron una mutación del gen PRKACA común en los adenomas suprarrenales e identificaron nuevas mutaciones en otros tipos de tumores suprarrenales.

Área de la Ciencia:

Endocrinología Endocrinología.
Genética La genética.
Oncología Oncología.

Sus antecedentes:

El síndrome de Cushing suprarrenal es el resultado de un exceso de producción de glucocorticoides.
Este exceso es a menudo causado por tumores adrenocorticales e hiperplasias, lo que lleva a trastornos metabólicos.

Objetivo del estudio:

Para identificar los impulsores genéticos del síndrome de Cushing suprarrenal.
Para investigar las mutaciones en los adenomas adrenocorticales (ACA) productores de cortisol, las hiperplasias adrenocorticales macronodulares independientes de la hormona adrenocorticotrópica (AIMAHs) y los oncocitomas adrenocorticales (ADOs).

Principales métodos:

Secuenciación del exoma entero de 49 pares de sangre y tumor.
Secuenciación del ARN de 44 tumores.

Principales resultados:

Se identificó una mutación de punto de acceso (L205R) en el gen PRKACA en el 69,2% de las ACAs, validada en el 65,5% de las 87 ACAs.
La mutación L205R activa la señalización de la proteína quinasa A (PKA), promoviendo la expresión génica.
Se descubrieron mutaciones recurrentes en DOT1L (AIMAH) y CLASP2 (ADO).

Conclusiones:

La mutación PRKACA L205R es un factor clave en la mayoría de las ACAs.
Las mutaciones DOT1L y CLASP2 representan nuevas alteraciones genéticas en AIMAH y ADO, respectivamente.
Estos hallazgos destacan los genes mutados potencialmente funcionales en el síndrome de Cushing suprarrenal, ofreciendo nuevos conocimientos sobre los mecanismos de la enfermedad.

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