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

Item Type:Article
Title:Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase in B cell lymphomas
Creators Name:Lopez, C. and Schleussner, N. and Bernhart, S.H. and Kleinheinz, K. and Sungalee, S. and Sczakiel, H.L. and Kretzmer, H. and Toprak, U.H. and Glaser, S. and Wagener, R. and Ammerpohl, O. and Bens, S. and Giefing, M. and Sanchez, J.C.G. and Apic, G. and Hubschmann, D. and Janz, M. and Kreuz, M. and Mottok, A. and Müller, J.M. and Seufert, J. and Hoffmann, S. and Korbel, J.O. and Russell, R.B. and Schule, R. and Trumper, L. and Klapper, W. and Radlwimmer, B. and Lichter, P. and Kuppers, R. and Schlesner, M. and Mathas, S. and Siebert, R.
Abstract:Histone methylation-modifiers, like 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 RNAseq studies, we here unravel KDM4C in chromosome 9p24, encoding a histone demethylase, to be recurrently altered. Focal structural variation was the main mechanism of KDM4C alterations, which was independent from 9p24 amplification. We identified KDM4C alterations also in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNAseq and genome sequencing data we predict KDM4C structural variants to result in loss-of-function. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as 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 putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas.
Publisher:Ferrata Storti Foundation
Date:28 April 2022
Official Publication:https://doi.org/10.3324/haematol.2021.280005
PubMed:View item in PubMed

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