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High prevalence of oncogenic MYD88 and CD79B mutations in primary testicular diffuse large B-cell lymphoma

Leukemia volume 28, pages 719–720 (2014)Cite this article

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Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous class of lymphomas, comprising of molecularly distinct subtypes that differ in gene-expression profile (GEP), genetic aberrations, clinical presentation and disease outcome.1, 2 Within this lymphoma class, primary testicular lymphoma (PTL) is a distinctive entity characterized by unique clinical and molecular features, including its exclusive manifestation in the immune-privileged microenvironment of the testis and frequent dissemination to the contralateral testis and the central nervous system (CNS).3, 4 Although the incidence of PTL has significantly increased over the last decades, there is at present no consensus on a standard therapeutic regimen.3, 4 A current GEP-based molecular classification of DLBCL distinguishes two main subtypes: activated B-cell-like (ABC) lymphoma and germinal-center B-cell-like lymphoma.1 PTLs belong to the ABC-DLBCL subtype that is characterized by constitutively active nuclear factor (NF)-κB signaling.1, 2 NF-κB pathway activation in DLBCL may result from oncogenic CARD11 mutations and/or of CD79 mutations causing chronic active B-cell receptor (BCR) signaling.5, 6, 7 In addition, somatically acquired mutations in MYD88, an adaptor protein that mediates toll-like receptor (TLR) and interleukin-1 receptor signaling were shown to promote NF-κB and JAK-STAT3 signaling in this lymphoma type.8 Intriguingly, recent studies indicate that the prevalence of oncogenic MYD88 mutations varies greatly among the ABC–DLBCL presenting at different anatomical sites: whereas MYD88 mutations show a high prevalence in primary-CNS-lymphomas (PCNSLs) as well as in lymphomas arising at some other extra-nodal sites, they are relatively uncommon in primary nodal and gastro-intestinal DLBCL.9, 10, 11 In a survey of genomic alterations in a large panel of DLBCL, we recently found an activating MYD88 mutation in 10 out of 14 PTLs studied,11 suggesting a high mutation prevalence. Here we extended these series to obtain robust evidence for a role of deregulated MYD88 signaling in PTLs.

The study material comprised a panel of 37 PTL diagnosed as DLBCLs according the World Health Organization classification, 14 of which have been reported previously.11 All tumors were extensively immuno-phenotyped, including antibodies against CD20, CD10, MUM1, BCL-2 and BCL-6, and tested for Epstein–Barr virus (EBV) expression by EBV-encoded RNA in-situ hybridization, and tested for translocations of BCL-2, BCL-6 and c-MYC by fluorescence in-situ hybridization (Supplementary Table 1).11 To detect somatic mutations in MYD88 and CD79B, a panel of allele-specific PCRs covering all major mutation (hot) spots8 was employed. As recently reported, this strategy permits efficient and sensitive detection of mutations using DNA extracted from the paraffin-embedded tissue, even in samples with relatively low tumor load.11 The detected mutations were verified by Sanger sequencing. Of the 37 PTLs studied, 25 tumors (68%) were found to harbor a MYD88 mutation (Supplementary Table 1). All these mutations concerned a leucine to proline exchange at position 265 (L265P). Among other MYD88 mutations reported, the L265P mutant has been shown to be biologically the most potent and was unique in its ability to organize a stable signaling complex containing phosphorylated IRAK1.8 These characteristics presumably explain its ‘hotspot’ status in lymphomas, including DLBCL and Waldenströms macroglobulinemia.8, 12 A CD79B mutation was found in 7 of the 37 PTLs (Supplementary Table 1). Interestingly, these tumors all harbored a coexisting MYD88 mutation.

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  1. M Spaargaren and S T Pals: These authors share last authorship.

Authors and Affiliations

  1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    W Kraan, M van Keimpema, H M Horlings, E J M Schilder-Tol, M E C M Oud, M Spaargaren & S T Pals

  2. Pathology Laboratory, Dordrecht, The Netherlands

    L A Noorduyn

  3. Department of Pathology, University Medical Center, Groningen, The Netherlands

    P M Kluin

  4. Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    M J Kersten

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Correspondence to S T Pals.

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Kraan, W., van Keimpema, M., Horlings, H. et al. High prevalence of oncogenic MYD88 and CD79B mutations in primary testicular diffuse large B-cell lymphoma. Leukemia 28, 719–720 (2014). https://doi.org/10.1038/leu.2013.348

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