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La caracterización de las firmas mutacionales en las líneas celulares de cáncer humano revela mutagenesis episódica

Mia Petljak¹, Ludmil B Alexandrov², Jonathan S Brammeld¹

¹Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.

|March 9, 2019

Resumen

Las líneas celulares de cáncer revelan patrones de mutación en curso. Las firmas de reparación y replicación del ADN permanecen estables, mientras que la edición de APOBEC muestra una actividad fluctuante y explosiva, que ofrece información sobre la evolución del genoma del cáncer.

Área de la Ciencia:

La genómica
Biología del cáncer
Biología molecular

Sus antecedentes:

Las mutaciones somáticas y sus firmas son la clave para entender los genomas del cáncer.
Estudios previos identificaron firmas mutacionales comunes en líneas celulares de cáncer y xenogéneros.

Objetivo del estudio:

Investigar patrones en curso de generación de firmas mutacionales en líneas celulares de cáncer a lo largo del tiempo.
Para determinar si los agentes mutagénicos externos o los procesos endógenos provocan la formación continua de la firma.

Principales métodos:

Cultivo de 1.001 líneas de células cancerosas humanas durante largos períodos.
Secuenciación de ADN de líneas celulares cultivadas para analizar patrones de mutación.
Comparación de las firmas generadas in vitro con las firmas conocidas in vivo.

Principales resultados:

Las firmas de las exposiciones externas como el humo del tabaco y la luz UV no se generaron in vitro.
Se generaron firmas relacionadas con la reparación y la replicación del ADN de manera consistente.
Las firmas de la citidina desaminasa APOBEC mostraron fluctuaciones temporales significativas con ráfagas episódicas.

Conclusiones:

Las líneas celulares de cáncer pueden modelar procesos mutacionales endógenos en curso.
La actividad de APOBEC se caracteriza por ráfagas, con factores iniciales poco claros que posiblemente involucran retrotransposones.
Estas líneas celulares sirven como modelos experimentales valiosos para estudiar los procesos mutacionales en los cánceres humanos.

Palabras clave:

Las desaminasas APOBEC líneas celulares de cáncer Mutagénesis episódica Las firmas mutacionales Trasplantes xenológicos

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