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

Author/s: Martí Duran-Ferrer, Guillem Clot, Ferran Nadeu, Renée Beekman, Tycho Baumann, Jessica Nordlund, Yanara Marincevic-Zuniga, Gudmar Lönnerholm, Alfredo Rivas-Delgado, Silvia Martin, Raquel Ordoñez, Giancarlo Castellano, Marta Kulis, Ana Queirós, Lee Seung-Tae, Joseph Wiemels, Romina Royo, Montserrat Puiggrós, Junyan Lu, Eva Gine, 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 and José Ignacio Martin-Subero


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.

Graphical summary

Data availablility

Description File size Download
DNA methylation matrix for 1799 samples and related metadata 6.1G Link
DNA methylation of curated 1595 samples and related metadata 4.9G Link
DNA methylation for CLL validation series and related metadata 1.8G Link
DNA methlation for MCL validation series and related metadata 465M Link
DNA methylation for DLBCL validation series and related metadata 137M Link

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Code availability

The source code is available at