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Las alteraciones estructurales que impulsan el cáncer de próstata resistente a la castración reveladas por la
Srinivas R Viswanathan1, Gavin Ha1, Andreas M Hoff2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
Cell
|June 19, 2018
Resumen
El cáncer de próstata metastásico resistente a la castración (mCRPC) muestra reorganizaciones frecuentes del locus AR, incluidas duplicaciones en tándem de un potenciador de AR, a diferencia de los cánceres de próstata primarios. Estos hallazgos revelan una genómica compleja de mCRPC y objetivos terapéuticos potenciales.
Área de la Ciencia:
- La genómica
- En el campo de la oncología
- Investigación del cáncer de próstata
Sus antecedentes:
- El cáncer de próstata metastásico resistente a la castración (mCRPC) es la causa principal de mortalidad por cáncer de próstata.
- Existen estudios limitados de secuenciación de genoma completo (WGS) para mCRPC, lo que dificulta la comprensión de su panorama genómico.
- La identificación de alteraciones genómicas en mCRPC es crucial para el desarrollo de tratamientos efectivos.
Objetivo del estudio:
- Investigar la arquitectura genómica del mCRPC utilizando la secuenciación de todo el genoma.
- Identificar las alteraciones genéticas recurrentes, especialmente en las regiones no codificantes, asociadas con la progresión de la mCRPC.
- Descubrir posibles objetivos terapéuticos para el mCRPC basados en nuevos hallazgos genómicos.
Principales métodos:
- Se realizó la secuenciación del genoma completo de lectura vinculada (WGS) en 23 muestras de biopsia de mCRPC.
- Se analizaron datos de secuenciación de ADN libre de células (cfDNA) de 86 pacientes con mCRPC.
- Reorganizaciones genómicas complejas caracterizadas, centradas en el locus AR y las regiones potenciadoras.
Principales resultados:
- Se observaron reorganizaciones frecuentes y complejas del locus AR en la mayoría de los casos de mCRPC.
- Se descubrieron duplicaciones en tándem altamente recurrentes de un potenciador de AR en el 70% - 87% de los casos de mCRPC, significativamente más altas que en los cánceres de próstata primarios (< 2%).
- Se identificó un subconjunto de casos con duplicación del potenciador AR o MYC vinculado a un fenotipo duplicador en tándem de todo el genoma impulsado por la inactivación de CDK12.
Conclusiones:
- El estudio revela una estructura genómica compleja y distinta en mCRPC, en particular con reorganizaciones del locus AR.
- Las duplicaciones recurrentes de potenciadores representan nuevos objetivos terapéuticos potenciales para el tratamiento con mCRPC.
- La exploración adicional del genoma no codificante de mCRPC puede descubrir eventos recurrentes adicionales y estrategias terapéuticas.
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