TY - JOUR
T1 - Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas
AU - Kataoka, Keisuke
AU - Miyoshi, Hiroaki
AU - Sakata, Seiji
AU - Dobashi, Akito
AU - Couronné, Lucile
AU - Kogure, Yasunori
AU - Sato, Yasuharu
AU - Nishida, Kenji
AU - Gion, Yuka
AU - Shiraishi, Yuichi
AU - Tanaka, Hiroko
AU - Chiba, Kenichi
AU - Watatani, Yosaku
AU - Kakiuchi, Nobuyuki
AU - Shiozawa, Yusuke
AU - Yoshizato, Tetsuichi
AU - Yoshida, Kenichi
AU - Makishima, Hideki
AU - Sanada, Masashi
AU - Onozawa, Masahiro
AU - Teshima, Takanori
AU - Yoshiki, Yumiko
AU - Ishida, Tadao
AU - Suzuki, Kenshi
AU - Shimada, Kazuyuki
AU - Tomita, Akihiro
AU - Kato, Motohiro
AU - Ota, Yasunori
AU - Izutsu, Koji
AU - Demachi-Okamura, Ayako
AU - Akatsuka, Yoshiki
AU - Miyano, Satoru
AU - Yoshino, Tadashi
AU - Gaulard, Philippe
AU - Hermine, Olivier
AU - Takeuchi, Kengo
AU - Ohshima, Koichi
AU - Ogawa, Seishi
N1 - Funding Information:
Acknowledgements We thank Miki Sagou and Takeshi Shirahari for technical assistance and all the members of the TENOMIC program. This work was supported by Grant-in-Aid from the Japan Agency for Medical Research and Development [Project for Cancer Research and Therapeutic Evolution (16cm0106501) and Practical Research for Innovative Cancer Control (17ck0106261)], National Cancer Center Research and Development Funds (29-E-3 and 30-A-1), the Naito Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Princess Takamatsu Cancer Research Fund, the Fondation ARC pour la recherche sur le cancer (20151203514), the France Lymphome Espoir association, and the GEFLUC Paris-Ile de France. LC was sponsored by a grant from ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé/National Alliance for Life Sciences and Health) within the framework of the Cancer Plan and by a fellowship awarded by the European Hematology Association and the Japanese Society of Hematology. The supercomputing resources were provided by the Human Genome Center, the Institute of Medical Science, The University of Tokyo.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85060671911&partnerID=8YFLogxK
U2 - 10.1038/s41375-019-0380-5
DO - 10.1038/s41375-019-0380-5
M3 - Article
C2 - 30683910
AN - SCOPUS:85060671911
VL - 33
SP - 1687
EP - 1699
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 7
ER -
