Oncotarget

Research Papers:

Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling

Ming Wang, Shaowei Zhang, Shih-Sung Chuang, Margaret Ashton-Key, Eguzkine Ochoa, Niccolo Bolli, George Vassiliou, Zifen Gao and Ming-Qing Du _

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Oncotarget. 2017; 8:17763-17770. https://doi.org/10.18632/oncotarget.14846

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Abstract

Ming Wang1,*, Shaowei Zhang2,1,*, Shih-Sung Chuang3, Margaret Ashton-Key4, Eguzkine Ochoa1, Niccolo Bolli5,6,7, George Vassiliou5, Zifen Gao2, Ming-Qing Du1

1Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK

2Department of Pathology, Health Science Centre, Peking University, Beijing, China

3Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan

4Department of Cellular Pathology, Southampton University Hospitals National Health Service Foundation Trust, Southampton, UK

5Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

6Department of Oncology and Onco-Hematology, University of Milan, Milan, Italy

7Department of Hematology and Pediatric Onco-Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

*These authors contributed equally to this work

Correspondence to:

Ming-Qing Du, email: mqd20@cam.ac.uk

Zifen Gao, email: wjshgao@bjmu.edu.cn

Keywords: AITL, WES, somatic mutation, oncogenic mechanism

Received: March 22, 2016     Accepted: January 19, 2017     Published: January 27, 2017

ABSTRACT

Angioimmunoblastic T cell lymphoma (AITL) originates from follicular helper T-cells and is characterised by a polymorphic infiltrate with the neoplastic T-cells forming small clusters around the follicle and high endothelial venules. Despite the recent advances in its phenotypic characterisation, the genetics and molecular mechanisms underlying AITL are not fully understood. In the present study, we performed whole exome sequencing in 9 cases of AITL from Taiwan (n = 6) and U.K. (n = 3). We confirmed frequent mutations in TET2 (9/9), DNMT3A (3/9), IDH2 (3/9), RHOA (3/9) and PLCG1 (2/9) as recently reported by others. More importantly, we identified mutations in TNFRSF21 (1/9), CCND3 (1/9) and SAMSN1 (1/9), which are not yet seen or strongly implicated in the pathogenesis of AITL. Among the pathogenic mutations identified in AITL, mutations in DNA methylation regulators TET2 and DNMT3A occur early in hematopoietic stem cells as shown by previous studies, and these genetic events enhance the self-renewal of hematopoietic stem cells, but are unlikely to have any major impact on T-cell differentiation. Mutations in RHOA, PLCG1 and TNFRSF21 (DR6), which encode proteins critical for T-cell biology, most likely promote T-cell differentiation and malignant transformation, consequently generating the malignant phenotype. Our findings extend the molecular insights into the multistage development of AITL.


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