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La cromotripsis en curso sustenta la complejidad del genoma del osteosarcoma y la evolución clonal

Jose Espejo Valle-Inclan¹, Solange De Noon², Katherine Trevers²

¹European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SA, UK.

|January 15, 2025

Resumen

La cromotripsis, un impulsor importante de la evolución del cáncer de hueso (osteosarcoma), crea cromosomas inestables y alimenta el crecimiento del tumor. Un nuevo mecanismo, la cromotripsis LTA, afecta específicamente al osteosarcoma, y los niveles de LOH en todo el genoma predicen los resultados de los pacientes.

Área de la Ciencia:

La genómica
Biología del cáncer
En el campo de la oncología

Sus antecedentes:

El osteosarcoma es el cáncer óseo primario más común, que afecta predominantemente a niños y adultos jóvenes.
La cromotripsis es una fuente significativa de inestabilidad genómica en varios tipos de cáncer.

Objetivo del estudio:

Investigar el papel y los mecanismos de la cromotripsis en el osteosarcoma.
Identificar nuevos procesos mutacionales y marcadores de pronóstico en el osteosarcoma de alto grado.

Principales métodos:

Secuenciación multiregional de todo el genoma de muestras de osteosarcoma.
Caracterización de los patrones de cromotripsis y las alteraciones genéticas asociadas.
Análisis de la pérdida de heterocigosidad en todo el genoma (LOH) como indicador de pronóstico.

Principales resultados:

La cromotripsis es un proceso mutacional en curso, subclonalmente adquirido en el 74% de los osteosarcomas, que conduce a mutaciones oncogénicas y heterogeneidad intra-tumoral.
Se identificó un nuevo mecanismo, la cromotripsia por pérdida-translocación-amplificación (LTA, por sus siglas en inglés), en aproximadamente el 50% de los osteosarcomas de alto grado, mediando la evolución puntuada a través de la inactivación de TP53 y la amplificación de oncogenes.
La cromotripsis LTA es particularmente frecuente en el osteosarcoma y es distinta de los cánceres con mutación TP53.
Se identificaron altos niveles de pérdida de heterocigosidad en todo el genoma (LOH) como un fuerte indicador de pronóstico para el osteosarcoma de alto grado.

Conclusiones:

La cromotripsis es un factor crítico de la evolución genómica y la heterogeneidad del osteosarcoma.
La cromotripsis LTA representa un mecanismo único de evolución puntuada en el osteosarcoma.
La LOH de todo el genoma es un biomarcador pronóstico valioso para el osteosarcoma de alto grado, que ayuda en la estratificación del riesgo y las decisiones de tratamiento.

Palabras clave:

TP53 (en inglés)ciclos de ruptura-fusión-puente Evolución del cáncer Inestabilidad cromosómica La cromotripsia reorganizaciones complejas del genoma ADN extracromosómico Inestabilidad genómica Osteosarcoma en el cuerpo duplicación de todo el genoma

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