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

Abstract

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 patient-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. Subsequently, 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 the differential diagnosis and prediction of clinical outcome.

• Authors: Martí Duran-Ferrer, Guillem Clot, Ferran Nadeu, Renée Beekman, Tycho Baumann, Jessica Nordlund, Yanara Marincevic-Zuniga, Gudmar Lönnerholm, Alfredo Rivas-Delgado, Silvia Martín, Raquel Ordoñez, Giancarlo Castellano, Marta Kulis, Ana C Queirós, Seung-Tae Lee, Joseph Wiemels, Romina Royo, Montserrat Puiggrós, Junyan Lu, Eva Giné, Sílvia Beà, Pedro Jares, Xabier Agirre, Felipe Prosper, Carlos López-Otín, Xosé S Puente, Christopher C Oakes, Thorsten Zenz, Julio Delgado, Armando López-Guillermo, Elías Campo, José Ignacio Martín-Subero
• Journal: Nature cancer (Nat Cancer) Vol. 1 Issue 11 Pg. 1066-1081 (11 2020) ISSN: 2662-1347 [Electronic] England
• PMID: 34079956 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Topics

• DNA Methylation (genetics)
• Epigenesis, Genetic (genetics)
• Epigenome (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasms