Open AccessImmune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS
Author(s) -
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 Ban,
Soumita Ghosh,
Stefanus Lie,
Seiichi Kato,
Shigeo Nakamura,
Emiko Takahashi,
YoungHyeh Ko,
Joseph D. Khoury,
ShihSung Chuang,
Rex Au-Yeung,
SooYong Tan,
Soon-Thye Lim,
ChoonKiat Ong,
Yong-Howe Ho,
Li Mei Poon,
Sanjay De Mel,
Anand D. Jeyasekharan,
WeeJoo Chng,
Franziska Otto,
Leticia Quintanilla-Martı́nez,
Federica Zanardi,
Fabio Iannelli,
Claudio Tripodo,
Jason J. Pitt,
Siok-Bian Ng
Publication year - 2022
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2021.280003
Subject(s) - lymphoma , microsatellite instability , t cell lymphoma , peripheral t cell lymphoma , biology , genome instability , cancer research , epstein–barr virus , epstein–barr virus infection , immune system , immunology , t cell , virus , gene , genetics , allele , microsatellite , dna , dna damage
Primary EBV+ 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 PTCL-NOS. Herein, we analyzed copy-number aberrations (n=77) with focus on global measures of genomic instability (GI) and homologous recombination deficiency (HRD) and performed gene expression (n=84) and EBV miRNA expression profiling (n=24) and targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed a significantly worse outcome of PTCL-EBV compared to PTCL-NOS (P=0.002) but not ENKTL. Remarkably, PTCL-EBV exhibited significantly lower GI and HRD scores compared to ENKTL and PTCL-NOS. Gene Set Enrichment Analysis revealed many immune-related pathways, interferon alpha/gamma response, and IL6_JAK_STAT3 signaling to be significantly upregulated in PTCL-EBV and correlated with lower GI-scores. We also identified NFκB-associated genes, BIRC3, NFκB1 (p50) and CD27, and their proteins to be upregulated in PTCLEBV. PTCL-EBV demonstrated mostly type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNAs 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 microsatellite stable. Overall, the poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNAs are distinctive features of PTCL-EBV. Our data support the consideration of PTCL-EBV as a distinct entity, provide novel insights into the disease pathogenesis and offer potential new therapeutic targets for this tumor.