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. 2013;8(2):e56741.
doi: 10.1371/journal.pone.0056741. Epub 2013 Feb 13.

A20 (TNFAIP3) deletion in Epstein-Barr virus-associated lymphoproliferative disorders/lymphomas

Midori Ando  1 , Yasuharu Sato, Katsuyoshi Takata, Junko Nomoto, Shigeo Nakamura, Koichi Ohshima, Tamotsu Takeuchi, Yorihisa Orita, Yukio Kobayashi, Tadashi Yoshino
Affiliations

A20 (TNFAIP3) deletion in Epstein-Barr virus-associated lymphoproliferative disorders/lymphomas

Midori Ando et al. PLoS One. 2013.

Abstract

A negative regulator of the nuclear factor (NF)-κB pathway, A20 (TNFAIP3), is inactivated in several types of lymphomas; particularly in diffuse large B-cell lymphoma (DLBCL), classical Hodgkin's lymphoma, and extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue. These findings suggest that the NF-κB activation is related to A20 inactivation. Recently, A20 inactivation has also been observed in Epstein-Barr virus (EBV)-related lymphomas; however, this occurrence has not been well investigated. Moreover, NF-κB is a key molecule in activated B-cell-like (ABC)-type DLBCL; EBV-associated DLBCL is of the ABC type. Therefore, we focused on A20 deletions in EBV-associated lymphoproliferative disorders/lymphomas. Using fluorescent in situ hybridization analysis, A20 deletions were identified in 4 of 13 samples from patients with pyothorax-associated lymphoma (PAL) (31%), 3 of 20 samples from nasal-type NK/T cell lymphomas (NKTLs) (15%), 1 of 8 samples of EBV-positive DLBCL of the elderly (DLBCL-e) (13%), but not in any of the 11 samples from individuals with methotrexate-related lymphoproliferative disorder (MTX-LPD) (0%). Among the samples with A20 deletions, EBV latent membrane protein 1 (LMP-1) expression was detected in all 4 of the PAL samples with A20 deletions and in the DLBCL-e sample with an A20 deletion, but not in any of the 3 NKTL samples. This finding indicated that A20 deletions were not directly related to the EBV latency pattern of lymphomas, although such deletions might be related to the diagnostic category. Immunohistologically, the A20 protein was absent in 2 (15%) of the 13 PAL samples, 1 (9%) of 11 MTX-LPD samples, and in none of the 20 NKTL (0%) or 8 DLBCL-e samples. In conclusion, A20 deletion and/or dysfunctional expression are frequently associated with PALs, and A20 abnormalities may be related to the pathogenesis of PAL.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. A20 monoallelic deletion in pyothorax-associated lymphoma.
(A) Diffuse proliferation of lymphoid cells, (hematoxylin-eosin stain, Olympus BX51, magnification ×200; inset ×400). (B) Positive signals in the nucleus of almost all tumor cells, (Epstein-Barr virus encoded RNA1, Olympus BX51, magnification ×400). (C) Positive signals in >50% of the tumor cells, (latent membrane protein-1, Olympus BX51, magnification ×400). (D) Monoallelic deletion of A20 detected by fluorescent in situ hybridization. A20 probe (orange) and chromosome 6 centromeric probe (green) (Olympus IX71, colors corrected after acquisition with Adobe Photoshop).
Figure 2
Figure 2. A20 biallelic deletion in nasal-type NK/T cell lymphoma.
(A) Medium-sized lymphoid cells with slightly irregular nuclei and mitosis, (hematoxylin-eosin stain, Olympus BX51, magnification ×200; inset ×400). (B) Positive signals in the nucleus of almost all tumor cells, (EBER1, Olympus BX51, magnification ×400). (C) Negative for latent membrane protein-1 (LMP-1) staining (LMP-1, Olympus BX51, magnification ×400). (D) Biallelic deletion of A20 detected by fluorescent in situ hybridization. A20 probe (orange) and chromosome 6 centromeric probe (green). (Olympus IX71, colors corrected after acquisition with Adobe Photoshop).
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