Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas

Haematologica. 2023 Feb 1;108(2):543-554. doi: 10.3324/haematol.2021.280005.


Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-offunction. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Histone Demethylases / genetics
  • Histone-Lysine N-Methyltransferase / genetics
  • Histones / metabolism
  • Homozygote
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / chemistry
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Lymphoma* / genetics
  • Lymphoma, B-Cell* / genetics
  • RNA
  • Sequence Deletion
  • Whole Genome Sequencing


  • Histones
  • Histone Demethylases
  • RNA
  • KDM4C protein, human
  • Jumonji Domain-Containing Histone Demethylases
  • PRDM9 protein, human
  • Histone-Lysine N-Methyltransferase

Grants and funding

Funding: This study was supported by the German Ministry of Science and Education (BMBF) in the framework of the ICGC MMML-Seq (01KU1002A-J) and ICGC DE-Mining (01KU1505G and 01KU1505E) projects. This work was also supported by the BMBF-funded Heidelberg Center for Human Bioinformatics (HD-HuB) within the German Network for Bioinformatics Infrastructure (de.NBI) (#031A537A, #031A537C). Former grant support for MMML by the Deutsche Krebshilfe (2003-2011) is gratefully acknowledged. CL was supported by an Alexander von Humboldt Foundation post-doctoral fellowship. RSi and MG received funding from the European Union's Horizon 2020 research and innovation program under grant agreement n. 952304. Former support to MG in the form of a FEBS long-term fellowship and a “Support for International Mobility of Scientists” fellowship of the Polish Ministry of Science and Higher Education is gratefully acknowledged.