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

Journal: Nature cancer
PMID: 34079956

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 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
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. maduran@clinic.cat.
  • Guillem Clot
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Ferran Nadeu
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Renée Beekman
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Tycho Baumann
    Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Madrid, Spain.
  • Jessica Nordlund
    Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Yanara Marincevic-Zuniga
    Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Gudmar Lönnerholm
    Department of Women's and Children's Health, Pediatrics, Uppsala University, Uppsala, Sweden.
  • Alfredo Rivas-Delgado
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Silvia Martín
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Raquel Ordoñez
    Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Madrid, Spain.
  • Giancarlo Castellano
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Marta Kulis
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Ana C Queirós
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Seung-Tae Lee
    Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea.
  • Joseph Wiemels
    Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA.
  • Romina Royo
    Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain.
  • Montserrat Puiggrós
    Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain.
  • Junyan Lu
    European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • Eva Giné
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Sílvia Beà
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Pedro Jares
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Xabier Agirre
    Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Madrid, Spain.
  • Felipe Prosper
    Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Madrid, Spain.
  • Carlos López-Otín
    Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Madrid, Spain.
  • Xosé S Puente
    Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Madrid, Spain.
  • Christopher C Oakes
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Thorsten Zenz
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Julio Delgado
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Armando López-Guillermo
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Elías Campo
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • José Ignacio Martín-Subero
    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. imartins@clinic.cat.

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