Detalle Publicación

The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome

Autores: Duran-Ferrer, M. (Autor de correspondencia); Clot, G.; Nadeu, F.; Beekman, R.; Baumann, T.; Nordlund, J.; Marincevic-Zuniga, Y.; Lonnerholm, G.; Rivas-Delgado, A.; Martín, S.; Ordóñez Ciriza, Raquel; Castellano, G.; Kulis, M.; Queirós, A. C.; Lee, S. T.; Wiemels, J.; Royo, R.; Puiggros, M.; Lu, J. Y.; Giné, E.; Bea, S.; Jares, P.; Aguirre Ena, Xabier; Prosper Cardoso, Felipe; López-Otín, C.; Puente, X. S.; Oakes, C. C.; Zenz, T.; Delgado, J.; López-Guillermo, A.; Campo, E.; Martín-Subero, J. I. (Autor de correspondencia)
Título de la revista: NATURE CANCER
ISSN: 2662-1347
Volumen: 1
Número: 11
Páginas: 1066 - 1081
Fecha de publicación: 2020
We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive individual-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. We construct a DNA-methylation-based mitotic clock, called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in differential diagnosis and the prediction of clinical outcome. Martin-Subero and colleagues analyze DNA methylation patterns in B-cell tumors and their normal cells of origin, and develop epiCMIT, a methylation-based mitotic clock with prognostic relevance.