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Análisis de factores somáticos no codificantes en 2.658 genomas enteros de cáncer

Esther Rheinbay^1,2,3, Morten Muhlig Nielsen⁴, Federico Abascal⁵

¹The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

|February 7, 2020

Resumen

Los investigadores analizaron regiones no codificantes en los genomas del cáncer, identificando nuevos impulsores del cáncer como las mutaciones TP53. Esto amplía nuestra comprensión más allá de los genes codificadores de proteínas para el descubrimiento de motores de cáncer.

Área de la Ciencia:

La genómica
Biología del cáncer
La bioinformática

Sus antecedentes:

El descubrimiento del conductor del cáncer tradicionalmente se centró en los genes codificadores de proteínas.
El papel de las regiones no codificantes en el cáncer sigue siendo menos explorado.
Los conjuntos de datos genómicos a gran escala ofrecen nuevas oportunidades para el descubrimiento.

Objetivo del estudio:

Analizar las mutaciones de los puntos impulsores y las variantes estructurales en las regiones del genoma del cáncer no codificantes.
Identificar nuevos factores no codificantes del cáncer utilizando métodos estadísticos avanzados.
Comparar la frecuencia de los conductores en las regiones codificadas frente a las no codificadas.

Principales métodos:

Análisis de 2.658 genomas completos de cáncer de los consorcios PCAWG y TCGA.
Desarrollo de una estrategia estadística rigurosa para combinar métodos de descubrimiento de conductores para mutaciones puntuales.
Aplicación de dos nuevos métodos para la identificación de factores de variación estructural, centrándose en los puntos de ruptura recurrentes y las yuxtaposiciones.

Principales resultados:

Confirmó los conductores conocidos de cáncer e interrogó a otros.
Se han identificado nuevos factores no codificantes, incluidas las mutaciones de la región 5' de TP53 y las mutaciones de la UTR 3' de NFKBIZ/TOB1.
Encontramos deleciones focales en BRD4 y reordenamientos en los loci del gen AKR1C.

Conclusiones:

Las regiones no codificantes albergan factores cancerígenos, aunque menos frecuentes que en los genes codificantes de proteínas.
Los análisis genómicos avanzados revelan nuevos mecanismos impulsores del cáncer.
Es probable que los estudios futuros con más genomas de cáncer descubran factores no codificantes adicionales.

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