Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas

Keisuke Kataoka,Lucile Couronné,Ayako Demachi-Okamura,Yosaku Watatani,Hiroaki Miyoshi,Tetsuichi Yoshizato,Kenji Nishida,Yasunori Kogure,Hiroko Tanaka,Kengo Takeuchi,Motohiro Kato,Kenichi Chiba,Tadao Ishida,Nobuyuki Kakiuchi,Yumiko Yoshiki,Olivier Hermine,Masashi Sanada,Yuichi Shiraishi,Yasunori Ota,Kenshi Suzuki,Takanori Teshima,Philippe Gaulard,Yusuke Shiozawa,Yuka Gion,Seiji Sakata,Akito Dobashi,Kenichi Yoshida,Satoru Miyano,Hideki Makishima,Yoshiki Akatsuka,Kazuyuki Shimada,Masahiro Onozawa,Yasuharu Sato,Koichi Ohshima,Koji Izutsu,Tadashi Yoshino,Akihiro Tomita,Seishi Ogawa

doi:10.1038/s41375-019-0380-5

Abstract

Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3′-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.

Highlights

Epstein-Barr virus (EBV) is one of the most prevalent human viruses
While PD-L1 structural variations (SVs) are present in a variety of solid cancers [13], no PD-L2-involving SVs were identified among 10,162 cancer samples from 32 tumor panels, for which RNA sequencing (RNA-seq) data were available from the Cancer Genome Atlas (TCGA)
These results suggest that PD-L1 is affected in a broad spectrum of human malignancies, whereas PD-L2 SVs are largely restricted to B-cell lymphomas, possibly reflecting the expression pattern of PD-1 ligands (Fig. 2b)

Summary

Introduction

Epstein-Barr virus (EBV) is one of the most prevalent human viruses. The interplay between EBV replication, latency, and immune control can be disrupted, evoking prolonged proliferation of EBV-infected lymphocytes and their malignant transformation [1, 2]. Extended author information available on the last page of the article. The oncogenic potential of EBV-encoded products has been extensively studied; they are known to mimic a variety of cellular factors involved in cell growth, transcription, and apoptosis, to usurp control of the pathways regulating diverse homeostatic cellular functions. Despite this oncogenic potential, the virus induces lymphoma only in a fraction of EBV-infected people, generally after a long latency period. EBV is thought to require somatic alterations in the cellular genome to cause lymphoma, whose impacts on the development of EBV-positive lymphomas have not fully been investigated, even though they might substantially differ from those involved in the development of EBV-negative lymphomas

Methods

Results

Conclusion