Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes
Siok-Bian Ng,
Tae-Hoon Chung,
Seiichi Kato,
Shigeo Nakamura,
Emiko Takahashi,
Young-Hyeh Ko,
Joseph D. Khoury,
C. Cameron Yin,
Richie Soong,
Anand D. Jeyasekharan,
Michal Marek Hoppe,
Viknesvaran Selvarajan,
Soo-Yong Tan,
Soon-Thye Lim,
Choon-Kiat Ong,
Maarja-Liisa Nairismägi,
Priyanka Maheshwari,
Shoa-Nian Choo,
Shuangyi Fan,
Chi-Kuen Lee,
Shih-Sung Chuang,
Wee-Joo Chng
Affiliations
Siok-Bian Ng
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore;Department of Pathology, National University Hospital, National University Health System, Singapore;Cancer Science Institute of Singapore, National University of Singapore
Tae-Hoon Chung
Cancer Science Institute of Singapore, National University of Singapore
Seiichi Kato
Department of Pathology and Laboratory Medicine, Nagoya University 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, USA
C. Cameron Yin
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Richie Soong
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore;Cancer Science Institute of Singapore, National University of Singapore
Anand D. Jeyasekharan
Cancer Science Institute of Singapore, National University of Singapore
Michal Marek Hoppe
Cancer Science Institute of Singapore, National University of Singapore
Viknesvaran Selvarajan
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore
Soo-Yong Tan
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore;Department of Pathology, National University Hospital, National University Health System, Singapore
Soon-Thye Lim
Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Division of Medical Oncology, National Cancer Center Singapore
Choon-Kiat Ong
Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore
Maarja-Liisa Nairismägi
Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore
Priyanka Maheshwari
Department of Pathology, National University Hospital, National University Health System, Singapore
Shoa-Nian Choo
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore
Shuangyi Fan
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore
Chi-Kuen Lee
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore
Shih-Sung Chuang
Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
Wee-Joo Chng
Cancer Science Institute of Singapore, National University of Singapore;Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System
The molecular biology of primary nodal T- and NK-cell lymphoma and its relationship with extranodal NK/T-cell lymphoma, nasal type is poorly understood. In this study, we assessed the relationship between nodal and extranodal Epstein-Barr virus-positive T/NK-cell lymphomas using gene expression profiling and copy number aberration analyses. We performed gene expression profiling and copy number aberration analysis on 66 cases of Epstein-Barr virus-associated T/NK-cell lymphoma from nodal and extranodal sites, and correlated the molecular signatures with clinicopathological features. Three distinct molecular clusters were identified with one enriched for nodal presentation and loss of 14q11.2 (TCRA loci). T/NK-cell lymphomas with a nodal presentation (nodal-group) were significantly associated with older age, lack of nasal involvement, and T-cell lineage compared to those with an extranodal presentation (extranodal-group). On multivariate analysis, nodal presentation was an independent factor associated with short survival. Comparing the molecular signatures of the nodal and extranodal groups it was seen that the former was characterized by upregulation of PD-L1 and T-cell-related genes, including CD2 and CD8, and downregulation of CD56, consistent with the CD8+/CD56-immunophenotype. PD-L1 and CD2 protein expression levels were validated using multiplexed immunofluorescence. Interestingly, nodal group lymphomas were associated with 14q11.2 loss which correlated with loss of TCR loci and T-cell origin. Overall, our results suggest that T/NK-cell lymphoma with nodal presentation is distinct and deserves to be classified separately from T/NK-cell lymphoma with extranodal presentation. Upregulation of PD-L1 indicates that it may be possible to use anti-PD1 immunotherapy in this distinctive entity. In addition, loss of 14q11.2 may be a potentially useful diagnostic marker of T-cell lineage.
