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A20 is targeted by promoter methylation, deletion and inactivating mutation in MALT lymphoma

Leukemia volume 24, pages 483–487 (2010)Cite this article

A Corrigendum to this article was published on 10 February 2010

Four recurrent chromosomal translocations, namely t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH, t(14;18)(q32;q21)/IGH-MALT1 and t(3;14)(p13;q32)/FOXP1-IGH, have been described in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). The oncogenic products of the first three translocations are believed to exert their oncogenic activity through activation of the transcription factor NF-κB, whereas the role of FOXP1 in lymphomagenesis remains to be investigated.1 These translocations occur at variable incidences in MALT lymphomas of different sites, and are rare or absent in the ocular adnexa, salivary glands and thyroid.1

To characterize the genetic makeup of MALT lymphoma lacking the above chromosomal translocations, we investigated the genomic profiles of translocation negative MALT lymphomas of the ocular adnexa and lung by array- comparative genomic hybridization (array-CGH) and identified A20 as the target of 6q23.3 deletion and TNF locus as a potential target of 6p21 gain exclusively in ocular adnexal cases.2 Subsequent fluorescence in situ hybridization screening showed that A20 deletion occurred preferentially in MALT lymphomas of the ocular adnexa, salivary glands and thyroid. In ocular adnexal cases, in which clinical information was available, A20 deletion was significantly associated with adverse clinical parameters, and this association was independent of the presence of other genetic abnormalities.2 Interestingly, among the 12 cases showing A20 deletion, 3 displayed a homozygous deletion, indicating complete inactivation of the gene. While preparing our manuscript, four independent studies reported biallelic inactivation of A20 by mutation and/or deletion in 67/381 (17.5%) B-cell lymphomas, including MALT lymphoma, diffuse large B-cell lymphoma and Hodgkin lymphoma.3, 4, 5, 6 A20, also known as TNF α-induced protein 3 (TNFAIP3), is a well-known negative regulator of the NF-κB activation pathway and can attenuate the NF-κB activity triggered by signaling from TNF and Toll-like receptors.7 In view of these findings, A20 could potentially act as a tumor suppressor gene. Nonetheless, it remains to be investigated whether A20, like other tumor suppressor genes, is also targeted for inactivation by promoter methylation and whether A20 abnormalities impact on clinical presentation and treatment response. In this study, we investigated A20 genetic and epigenetic abnormalities, and also examined the clinical impact of A20 inactivation in MALT lymphoma.

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Acknowledgements

We thank Dr Yoko Ito, Cambridge Research Institute, for technical and analytical advice on pyrosequencing, and Dr Ash Ibrahim and Miss Ana Luisa De Silva for helpful discussions. This work was supported by the Elimination of Leukemia Fund (ELF/7/3/8), UK, the Lady Tata Memorial Trust, and Leukemia Research, UK (LRF06061).

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Authors and Affiliations

  1. Department of Pathology, University of Cambridge, Cambridge, UK

    E Chanudet, Y Huang, K Ichimura, G Dong, R A Hamoudi & M-Q Du

  2. Department of Medical Oncology, Christie NHS Foundation Trust and University of Manchester, Manchester, UK

    J Radford

  3. Department of Histopathology, Royal Marsden Hospital, London, UK

    A C Wotherspoon

  4. Department of Histopathology, University College London, London, UK

    P G Isaacson

  5. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    J Ferry

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  1. E Chanudet
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Correspondence to E Chanudet or M-Q Du.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Chanudet, E., Huang, Y., Ichimura, K. et al. A20 is targeted by promoter methylation, deletion and inactivating mutation in MALT lymphoma. Leukemia 24, 483–487 (2010). https://doi.org/10.1038/leu.2009.234

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