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Analysis of mutational signatures in exomes from B-cell lymphoma cell lines suggest APOBEC3 family members to be involved in the pathogenesis of primary effusion lymphoma

Leukemia volume 29, pages 1612–1615 (2015)Cite this article

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Primary effusion lymphoma (PEL) is a rare large B-cell neoplasm particularly affecting immunodeficient hosts with an increased incidence in young or middle-aged males infected with the HIV.1 The clinical outcome of patients with PEL is unfavorable with a median survival of <6 months.1 PEL has been closely associated with human herpes virus 8 (HHV8, previously called Kaposi sarcoma herpesvirus) infection.1 In some cases a coinfection of HHV8 with the Epstein–Barr Virus (EBV) has been described.1 HHV8 encodes various genes homologous to cellular genes that have proliferative and anti-apoptotic functions.2 Although HHV8 is supposed to be a major driver of PEL, it alone is not sufficient for a full-blown lymphomagenesis.2 PEL usually shows complex karyotypes with many chromosomal aberrations.3 This chromosomal complexity might be driven by the viral infection and lead to genetic alterations cooperating with HHV8 in PEL lymphomagenesis.4

The human innate immune defense against exogenous viruses comprises cytidine deaminases of the ApoB mRNA-editing catalytic subunit (APOBEC) family that are able to edit DNA and/or RNA by deaminating cytosins to uracil.5 The APOBEC family comprises APOBEC1, APOBEC3 (including APOBEC3A-D and APOBEC3F-H), APOBEC4 and activation-induced cytidine deaminase (AID). The APOBEC3 proteins are implicated in natural defense against a variety of viruses associated with lymphomagenesis including human T-cell leukemia virus and EBV.5 However, mitochondrial and nuclear DNA can also be targeted by APOBEC3 proteins.6 APOBEC3 activity has been suggested to contribute to tumorigenesis by introducing somatic mutations through C>U deamination.7 The specificity of APOBEC activity in modifying DNA can be detected as a mutational signature in cancer genomes when analyzing whole-exome and whole-genome sequencing data.8 Similarly, footprints of other mutational processes can also be traced in cancer genomes. Indeed, in a recent analysis of somatic mutations in 7042 cancers derived from 30 different classes of tumors, we extracted 27 distinct signatures of mutational processes including a signature attributed to the APOBEC family of cytidine deaminases.8 Like in other tumor entities, this signature was detected in whole-genome sequencing data from mature B-cell lymphomas including Burkitt (BL), follicular and diffuse large B-cell lymphomas (DLBCL).

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Acknowledgements

This study was supported by the German Ministry of Education and Science (BMBF) through the International Cancer Genome Consortium (ICGC) MMML-Seq Project (01KU1002A to 01KU1002J) and the e:Bio ‘MMML-MYC-SYS’ project (BMBF FKZ 0316166). RW is supported by a Christoph-Schubert-Award of the KinderKrebsInitiative Buchholz/Holm-Seppensen. Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the US Department of Energy.

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Authors and Affiliations

  1. Institute of Human Genetics, University Hospital Schleswig-Holstein, Christian-Albrechts-University Kiel, Campus Kiel, Kiel, Germany

    R Wagener, A Haake, J Richter & R Siebert

  2. Cancer Genome Project, Wellcome Trust Cancer Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK

    L B Alexandrov, G R Bignell & U McDermott

  3. Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, USA

    L B Alexandrov

  4. Institute for Neuropathology, University Hospital of Cologne, Cologne, Germany

    M Montesinos-Rongen

  5. Division of Theoretical Bioinformatics, Deutsches Krebsforschungszentrum Heidelberg (DKFZ), Heidelberg, Germany

    M Schlesner

  6. Leibniz-Institute DSMZ- German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany

    H G Drexler

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  1. R Wagener
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Wagener, R., Alexandrov, L., Montesinos-Rongen, M. et al. Analysis of mutational signatures in exomes from B-cell lymphoma cell lines suggest APOBEC3 family members to be involved in the pathogenesis of primary effusion lymphoma. Leukemia 29, 1612–1615 (2015). https://doi.org/10.1038/leu.2015.22

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