Scientific publications
The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome. Scientific Publication
Martí Duran-Ferrer 1 2 , Guillem Clot 3 4 , Ferran Nadeu 3 4 , Renée Beekman 3 4 , Tycho Baumann 4 5 , Jessica Nordlund 6 , Yanara Marincevic-Zuniga 6 , Gudmar Lönnerholm 7 , Alfredo Rivas-Delgado 3 5 , Silvia Martín 3 4 , Raquel Ordoñez 4 8 , Giancarlo Castellano 3 , Marta Kulis 3 , Ana C Queirós 3 , Seung-Tae Lee 9 , Joseph Wiemels 10 , Romina Royo 11 , Montserrat Puiggrós 11 , Junyan Lu 12 , Eva Giné 3 4 5 , Sílvia Beà 3 4 13 , Pedro Jares 3 4 13 , Xabier Agirre 4 8 , Felipe Prosper 4 8 14 , Carlos López-Otín 4 15 , Xosé S Puente 4 15 , Christopher C Oakes 13 , Thorsten Zenz 13 16 , Julio Delgado 3 4 5 , Armando López-Guillermo 3 4 5 , Elías Campo 3 4 17 , José Ignacio Martín-Subero 18 19 20 21
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.
CITATION Nat Cancer. 2020 Nov;1(11):1066-1081. doi: 10.1038/s43018-020-00131-2. Epub 2020 Nov 2
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