Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS

作者：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, Young Hyeh Ko, Joseph D. Khoury, Shih‐Sung Chuang, Rex 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‐Martínez, Federica Zanardi, Fabio Iannelli, Claudio Tripodo, Jason J. Pitt, Siok‐Bian Ng · 发表于：Haematologica · 年份：2022 · DOI：10.3324/haematol.2021.280003 · 被引用次数：83 · 研究领域：Viral-associated cancers and disorders、Lymphoma Diagnosis and Treatment、Immune Cell Function and Interaction

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 al...