Nordlund, J. (Jessica)

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    The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome
    (2020) López-Guillermo, A. (Armando); Jares, P. (Pedro); Nadeu, F. (Ferran); Beekman, R. (Renée); Royo, R. (Romina); Zenz, T. (Thorsten); Delgado, J. (Julio); Seung-Tae, L. (Lee); Kulis, M. (Marta); Bea, S. (Silvia); Baumann, T. (Tycho); Castellano, G. (Giancarlo); Marincevic-Zuniga, Y. (Yanara); Wiemels, J. (Joseph); Raquel; Puente, X.S. (Xosé S.); Campo, E. (Elías); Nordlund, J. (Jessica); Lonnerholm, G. (Gudmar); Duran-Ferrer, M. (Martí); Queirós, A. (Ana); Rivas-Delgado, A. (Alfredo); Puiggros, M. (Montserrat); Prosper-Cardoso, F. (Felipe); Giné, E. (Eva); Clot, G. (Guillem); Aguirre-Ena, X. (Xabier); Oakes, C.C. (Christopher C.); López-Otín, C. (Carlos); Lu, J. (Junyan); Martín, S. (Silvia); Martin-Subero, J.I. (Jose Ignacio)
    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.