FISH检测经典霍奇金淋巴瘤TNFAIP3基因缺失及其与EB病毒感染的相关性

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Abstract

目的

研究经典霍奇金淋巴瘤（CHL）中肿瘤坏死因子α诱导蛋白3(TNFAIP3）基因及其编码的A20蛋白表达情况，并分析其与Epstein-Barr病毒（EBV）感染的相关性。

方法

收集54例CHL患者的病理标本及临床资料，选取肿瘤细胞丰富区制作组织芯片。应用免疫组织化学染色法检测EBV编码的潜伏膜蛋白1(LMP-1），原位杂交法检测EBV编码的RNA（EBER1/2）以明确EBV感染状态。使用位点特异性间期荧光原位杂交（FISH）法检测TNFAIP3基因表达，免疫组织化学染色法检测A20蛋白表达。使用SPSS17.0统计学软件包进行数据分析。

结果

LMP-1、EBER1/2阳性率均为25.9%（14/54），两者符合率为100%。27.8%（15/54）的标本存在A20表达丢失，20.4%（10/49）的标本存在TNFAIP3杂合或纯合缺失。两种方法的检测结果显示存在明显不一致，TNFAIP3缺失伴A20丢失仅有1例。此外，EBV感染阴性与A20丢失及TNFAIP3缺失无相关性（ P>0.05）。

结论

EBV阳性和阴性CHL病例均存在TNFAIP3基因和（或）A20蛋白表达丢失。FISH和免疫组织化学染色两种方法结果不一致，可能与技术因素有关。

Translated abstract

Objective

To investigate the TNFAIP3/A20 abnormalities and its association with Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (CHL).

Methods

Formalin-fixed, paraffinembedded tissue blocks of 54 CHL patients were collected and subjected to the construction of tissue microarray (TMA) for further analyses. EBV status was evaluated by in situ hybridization (ISH) for EBER1/2 and immunohistochemistry (IHC) with anti-LMP-1 antibody. Fluorescence in situ hybridization (FISH) and IHC were performed to determine the copy number alterations of TNFAIP3 and A20 protein expression respectively.

Results

The concordance rate of IHC for LMP-1 and ISH for EBER1/2 was100%, and 25.9% (14/54) cases were identified with EBV infection. Immunohistochemistry analysis demonstrated 27.8% (15/54) cases with A20 expression deficiency. Of the 54 cases tested for A20 expression, 49 cases were simultaneously analyzed by FISH, which showed 10 (20.4%) cases harboring TNFAIP3 deletion. However, discrepancy was observed between the results of A20 by IHC and TNFAIP3 deletion by FISH. Only 1 case with TNFAIP3 deletion demonstrated complete loss of A20 immunoreactivity. In addition, comparison of the frequency of either A20 expression loss or TNFAIP3 deletion between EBV-positive and-negative cases did not reveal any significance ( P>0.05).

Conclusion

TNFAIP3 deletion could be observed in both EBV-positive and -negative CHL cases. A20 expression by IHC could not confirm TNFAIP3 deletion by FISH, which might be related to the technical issues.

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Most cited references 16

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Frequent inactivation of A20 in B-cell lymphomas.

Motohiro Kato, Masashi Sanada, Itaru Kato … (2009)

A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappaB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.

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TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma

Roland PH Schmitz, Martin Leo Hansmann, Verena Bohle … (2009)

Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), are dependent on constitutive activation of nuclear factor κB (NF-κB). NF-κB activation through various stimuli is negatively regulated by the zinc finger protein A20. To determine whether A20 contributes to the pathogenesis of cHL, we sequenced TNFAIP3, encoding A20, in HL cell lines and laser-microdissected HRS cells from cHL biopsies. We detected somatic mutations in 16 out of 36 cHLs (44%), including missense mutations in 2 out of 16 Epstein-Barr virus–positive (EBV+) cHLs and a missense mutation, nonsense mutations, and frameshift-causing insertions or deletions in 14 out of 20 EBV− cHLs. In most mutated cases, both TNFAIP3 alleles were inactivated, including frequent chromosomal deletions of TNFAIP3. Reconstitution of wild-type TNFAIP3 in A20-deficient cHL cell lines revealed a significant decrease in transcripts of selected NF-κB target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-κB activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-κB activity, as a novel tumor suppressor gene in cHL and PMBL. The significantly higher frequency of TNFAIP3 mutations in EBV− than EBV+ cHL suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis.

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Hodgkin lymphoma.

Martin Leo Hansmann, Andreas Engert, Ralf Küppers (2012)

Hodgkin lymphoma (HL), a B cell-derived cancer, is one of the most common lymphomas. In HL, the tumor cells--Hodgkin and Reed-Sternberg (HRS) cells--are usually very rare in the tissue. Although HRS cells are derived from mature B cells, they have largely lost their B cell phenotype and show a very unusual co-expression of markers of various hematopoietic cell types. HRS cells show deregulated activation of multiple signaling pathways and transcription factors. The activation of these pathways and factors is partly mediated through interactions of HRS cells with various other types of cells in the microenvironment, but also through genetic lesions. The transforming events involved in the pathogenesis of HL are only partly understood, but mutations affecting the NF-κB and JAK/STAT pathways are frequent. The dependency of HRS cells on microenvironmental interactions and deregulated signaling pathways may offer novel strategies for targeted therapies.

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Author and article information

Journal

Journal ID (nlm-ta): Zhonghua Xue Ye Xue Za Zhi

Journal ID (iso-abbrev): Zhonghua Xue Ye Xue Za Zhi

Journal ID (publisher-id): CJH

Title: Chinese Journal of Hematology

Publisher: Editorial office of Chinese Journal of Hematology (No. 288, Nanjing road, Heping district, Tianjin )

ISSN (Print): 0253-2727

ISSN (Electronic): 2707-9740

Publication date (Print): December 2016

Volume: 37

Issue: 12

Pages: 1060-1064

Affiliations

[1]100191 北京大学基础医学院病理学系血液病理研究室（时云飞、高子芬、刘翠苓、李敏、刘校龙、黄欣）；北京大学肿瘤医院（林冬梅、周立新、赖玉梅）

Author notes

通信作者：黄欣，Email： huangxin@ 123456bjmu.edu.cn

Corresponding author: Huang Xin, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Email: huangxin@ 123456bjmu.edu.cn

Article

Publisher ID: cjh-37-12-1060

DOI: 10.3760/cma.j.issn.0253-2727.2016.12.010

PMC ID: 7348485

PubMed ID: 28088970

SO-VID: a436f440-969f-4307-b3f0-90fd36cdbb6f

License:

This work is licensed under a Creative Commons Attribution 3.0 License (CC-BY-NC). The Copyright own by Publisher. Without authorization, shall not reprint, except this publication article, shall not use this publication format design. Unless otherwise stated, all articles published in this journal do not represent the views of the Chinese Medical Association or the editorial board of this journal.

History

Date received : 16 August 2016

Funding

基金项目：国家自然科学基金（81201859）

Fund program: National Natural Science Foundation of China（81201859）

FISH检测经典霍奇金淋巴瘤TNFAIP3基因缺失及其与EB病毒感染的相关性 Translated title: TNFAIP3 deletion status in classical Hodgkin lymphoma and its relation to Epstein-Barr virus

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Most cited references 16

Frequent inactivation of A20 in B-cell lymphomas.

TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma

Hodgkin lymphoma.

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