Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS
Cho Mar Myint Wai,
Shangying Chen,
The Phyu,
Shuangyi Fan,
Sai Mun Leong,
Wenning Zheng,
Louis Ching Yi Low,
Shoa-Nian Choo,
Chi-Kuen Lee,
Tae-Hoon Chung,
Kenneth Hon Kim Ban,
Soumita Ghosh,
Stefanus Lie,
Seiichi Kato,
Shigeo Nakamura,
Emiko Takahashi,
Young-Hyeh Ko,
Joseph D. Khoury,
Shih-Sung Chuang,
Rex K.H. Au-Yeung,
Soo-Yong Tan,
Soon-Thye Lim,
Choon-Kiat Ong,
Yong-Howe Ho,
Li Mei Poon,
Sanjay de Mel,
Anand D. Jeyasekharan,
Wee-Joo Chng,
Franziska Otto,
Leticia Quintanilla-Martinez,
Federica Zanardi,
Fabio Iannelli,
Claudio Tripodo,
Jason J. Pitt,
Siok-Bian Ng
Affiliations
Cho Mar Myint Wai
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Shangying Chen
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
The Phyu
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Shuangyi Fan
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Sai Mun Leong
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Wenning Zheng
Cancer Science Institute of Singapore, National University of Singapore, Singapore
Louis Ching Yi Low
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Shoa-Nian Choo
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Chi-Kuen Lee
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Tae-Hoon Chung
Cancer Science Institute of Singapore, National University of Singapore, Singapore
Kenneth Hon Kim Ban
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Soumita Ghosh
Cancer Science Institute of Singapore, National University of Singapore, Singapore
Stefanus Lie
Cancer Science Institute of Singapore, National University of Singapore, Singapore
Seiichi Kato
Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan; Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
Shigeo Nakamura
Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
Emiko Takahashi
Department of Pathology, Aichi Medical University Hospital, Nagakute, Japan
Young-Hyeh Ko
Department of Pathology, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea
Joseph D. Khoury
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
Shih-Sung Chuang
Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
Rex K.H. Au-Yeung
Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China
Soo-Yong Tan
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Pathology, National University Hospital, National University Health System, Singapore
Soon-Thye Lim
Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Singapore; Division of Medical Oncology, National Cancer Centre Singapore, Singapore
Choon-Kiat Ong
Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore; Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
Yong-Howe Ho
Department of Pathology, Tan Tock Seng Hospital, Singapore
Li Mei Poon
Department of Hematology-Oncology, National University Cancer Institute Singapore, National University Hospital, National University Health System, Singapore
Sanjay de Mel
Department of Hematology-Oncology, National University Cancer Institute Singapore, National University Hospital, National University Health System, Singapore
Anand D. Jeyasekharan
Cancer Science Institute of Singapore, National University of Singapore, Singapore
Wee-Joo Chng
Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Hematology-Oncology, National University Cancer Institute Singapore, National University Hospital, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Franziska Otto
Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany
Leticia Quintanilla-Martinez
Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany
Federica Zanardi
Bioinformatics Unit, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy
Fabio Iannelli
Bioinformatics Unit, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy
Claudio Tripodo
Tumor Immunology Unit, University of Palermo School of Medicine, Palermo, Italy
Jason J. Pitt
Cancer Science Institute of Singapore, National University of Singapore, Singapore
Siok-Bian Ng
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pathology, National University Hospital, National University Health System, Singapore
Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copynumber aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCLEBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.
