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Mutaciones somáticas convergentes en los genes del metabolismo en la enfermedad hepática crónica

Stanley W K Ng¹, Foad J Rouhani^1,2, Simon F Brunner¹

¹Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK.

|October 14, 2021

Resumen

Las mutaciones somáticas en genes clave del metabolismo como FOXO1, CIDEB y GPAM se observan con frecuencia en enfermedades hepáticas crónicas, incluida la enfermedad hepática grasa relacionada con el alcohol y no alcohólica.

Área de la Ciencia:

La genómica
Hepatología
Biología del cáncer

Sus antecedentes:

La progresión de la enfermedad hepática crónica a carcinoma hepatocelular implica mutaciones somáticas en los genes del cáncer.
Las cargas de mutación somática y las expansiones clonales son más altas en la enfermedad hepática crónica que en el hígado normal, facilitando la selección positiva.
La configuración del paisaje genómico en la enfermedad hepática está influenciada por presiones de selección positivas.

Objetivo del estudio:

Analizar mutaciones somáticas en 1.590 genomas de 34 muestras de hígado, incluidos controles sanos, enfermedad hepática relacionada con el alcohol (ARLD) y enfermedad hepática grasa no alcohólica (NAFLD).
Investigar el papel de genes específicos, como FOXO1, CIDEB y GPAM, en el contexto de las mutaciones de la enfermedad hepática.
Identificar patrones de evolución convergente en mutaciones somáticas dentro de contextos de enfermedad hepática.

Principales métodos:

Secuenciación de todo el genoma de 1.590 muestras en tejidos hepáticos sanos, ARLD y NAFLD.
Análisis de mutaciones somáticas en 34 muestras de hígado para identificar genes afectados y puntos calientes de mutación.
Investigación de la evolución clonal y los patrones de expansión asociados con mutaciones genéticas específicas.

Principales resultados:

Siete de los 29 pacientes con enfermedad hepática tenían mutaciones en FOXO1, un factor clave de transcripción de la señalización de la insulina, que afectaba a un solo punto de acceso y afectaba a la exportación nuclear.
Se observó una evolución convergente en las mutaciones FOXO1 (punto caliente S22W), con hasta nueve clones de hepatocitos independientes por paciente.
CIDEB y GPAM, implicados en el metabolismo lipídico, también mostraron un exceso de mutaciones con una evolución convergente frecuente (hasta 14 y 7 clones por paciente, respectivamente).
Las mutaciones genéticas del metabolismo fueron generalizadas a través de segmentos hepáticos, aumentaron el tamaño del clon y ocurrieron tanto en ARLD como en NAFLD, pero fueron raras en el carcinoma hepatocelular.

Conclusiones:

Los reguladores maestros de las vías metabólicas son frecuentemente el objetivo de las mutaciones somáticas convergentes en ARLD y NAFLD.
La evolución convergente de las mutaciones en los genes metabólicos sugiere fuertes presiones selectivas en la enfermedad hepática crónica.
Estos hallazgos resaltan el papel de la desregulación metabólica y las mutaciones somáticas en la patogénesis de la enfermedad hepática crónica.

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