Journal
LEUKEMIA
Volume 33, Issue 7, Pages 1687-1699Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41375-019-0380-5
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Funding
- Japan Agency for Medical Research and Development [16cm0106501, 17ck0106261]
- National Cancer Center Research and Development Funds [29-E-3, 30-A-1]
- Naito Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Princess Takamatsu Cancer Research Fund
- Fondation ARC pour la recherche sur le cancer [20151203514]
- France Lymphome Espoir association
- GEFLUC Paris-Ile de France
- ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Sante/National Alliance for Life Sciences and Health)
- European Hematology Association
- Japanese Society of Hematology
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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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