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La diversidad espacial y temporal en los procesos de inestabilidad genómica define la evolución del cáncer de pulmón

Elza C de Bruin¹, Nicholas McGranahan², Richard Mitter³

¹Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK.

Science (New York, N.Y.)

|October 11, 2014

Resumen

El análisis genómico del cáncer de pulmón de células no pequeñas (CPNPC) revela una evolución ramificada y una heterogeneidad intratumor significativa. Estos complejos cambios genómicos, incluyendo mutaciones conductor e inestabilidad, contribuyen a los desafíos en el tratamiento del NSCLC.

Área de la Ciencia:

Oncología Oncología.
La genómica es la genómica.
Cáncer Evolución Evolución del cáncer.

Sus antecedentes:

El cáncer de pulmón de células no pequeñas (CPNPC) tiene un mal pronóstico, en parte debido a complejas alteraciones genómicas.
Comprender los cambios genómicos espaciales y temporales en el NSCLC es crucial para mejorar los resultados del tratamiento.

Objetivo del estudio:

Para diseccionar la evolución genómica espacial y temporal del NSCLC humano.
Identificar los fundamentos genómicos de la heterogeneidad del NSCLC y su impacto en el pronóstico.

Principales métodos:

Secuenciación de 25 regiones espacialmente distintas de siete tumores de NSCLC operables.
Análisis de las alteraciones del número de copias, translocaciones y mutaciones, incluida la actividad asociada con APOBEC.
Análisis comparativo de los patrones de mutación en los tumores de fumadores actuales y antiguos.

Principales resultados:

Evidencia de patrones evolutivos ramificados en el NSCLC, con mutaciones del controlador que aparecen en diferentes etapas.
Manifiesta heterogeneidad intratumor en las alteraciones genómicas, incluyendo cambios en el número de copias y translocaciones.
Cambios en las firmas de mutación a lo largo del tiempo en los fumadores, con una disminución en las mutaciones relacionadas con el tabaquismo y un aumento en las mutaciones asociadas con APOBEC.
Identificación de eventos de duplicación del genoma en ex fumadores anteriores a la diversificación subclonal, lo que sugiere un largo período de latencia.

Conclusiones:

Las mutaciones impulsoras regionales distintas y la inestabilidad generalizada del genoma en el NSCLC complican las estrategias de tratamiento.
La naturaleza heterogénea y dinámica de la evolución del NSCLC presenta desafíos significativos para el éxito terapéutico.
Comprender estas dinámicas evolutivas es clave para desarrollar tratamientos más efectivos para el NSCLC.

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