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

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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-c...

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Main Authors: López, Cristina (Author) , Schleußner, Nikolai (Author) , Bernhart, Stephan H. (Author) , Kleinheinz, Kortine (Author) , Sungalee, Stephanie (Author) , Sczakiel, Henrike L. (Author) , Kretzmer, Helene (Author) , Toprak, Umut (Author) , Glaser, Selina (Author) , Wagener, Rabea (Author) , Ammerpohl, Ole (Author) , Bens, Susanne (Author) , Giefing, Maciej (Author) , González Sánchez, Juan Carlos (Author) , Apic, Gordana (Author) , Hübschmann, Daniel (Author) , Janz, Martin (Author) , Kreuz, Markus (Author) , Mottok, Anja (Author) , Muller, Judith M. (Author) , Seufert, Julian (Author) , Hoffmann, Steve (Author) , Korbel, Jan Oliver (Author) , Russell, Robert B. (Author) , Schule, Roland (Author) , Trumper, Lorenz (Author) , Klapper, Wolfram (Author) , Radlwimmer, Bernhard (Author) , Lichter, Peter (Author) , Kuppers, Ralf (Author) , Schlesner, Matthias (Author) , Mathas, Stephan (Author) , Siebert, Reiner (Author)
Format: Article (Journal)
Language:English
Published: February, 2023
In: Haematologica
Year: 2023, Volume: 108, Issue: 2, Pages: 543-554
ISSN:1592-8721
DOI:10.3324/haematol.2021.280005
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3324/haematol.2021.280005
Verlag, lizenzpflichtig, Volltext: https://haematologica.org/article/view/haematol.2021.280005
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Author Notes:Cristina Lopez, Nikolai Schleussner, Stephan H. Bernhart, Kortine Kleinheinz, Stephanie Sungalee, Henrike L. Sczakiel, Helene Kretzmer, Umut H. Toprak, Selina Glaser, Rabea Wagener, Ole Ammerpohl, Susanne Bens, Maciej Giefing, Juan C. Gonzalez Sanchez, Gordana Apic, Daniel Hübschmann, Martin Janz, Markus Kreuz, Anja Mottok, Judith M. Müller, Julian Seufert, Steve Hoffmann, Jan O. Korbel, Robert B. Russell, Roland Schule, Lorenz Trumper, Wolfram Klapper, Bernhard Radlwimmer, Peter Lichter, Ralf Kuppers, Matthias Schlesner, Stephan Mathas and Reiner Siebert and members of the ICGC MMML-Seq Consortium

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520 |a 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. 
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