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

• Published in: Leukemia 2019-07, Vol.33 (7), p.1687-1699
• Main Authors: Kataoka, Keisuke, Miyoshi, Hiroaki, Sakata, Seiji, Dobashi, Akito, Couronné, Lucile, Kogure, Yasunori, Sato, Yasuharu, Nishida, Kenji, Gion, Yuka, Shiraishi, Yuichi, Tanaka, Hiroko, Chiba, Kenichi, Watatani, Yosaku, Kakiuchi, Nobuyuki, Shiozawa, Yusuke, Yoshizato, Tetsuichi, Yoshida, Kenichi, Makishima, Hideki, Sanada, Masashi, Onozawa, Masahiro, Teshima, Takanori, Yoshiki, Yumiko, Ishida, Tadao, Suzuki, Kenshi, Shimada, Kazuyuki, Tomita, Akihiro, Kato, Motohiro, Ota, Yasunori, Izutsu, Koji, Demachi-Okamura, Ayako, Akatsuka, Yoshiki, Miyano, Satoru, Yoshino, Tadashi, Gaulard, Philippe, Hermine, Olivier, Takeuchi, Kengo, Ohshima, Koichi, Ogawa, Seishi
• Format: Article
• Language: English
• Subjects: 13/31; 13/51; 45/23; 45/91; 631/67/1858; 631/67/580/1884; 631/67/69; Apoptosis; B-cell lymphoma; B7-H1 Antigen - genetics; Biomarkers, Tumor - genetics; Cancer Research; Care and treatment; Cell-mediated immunity; Clonal selection; Critical Care Medicine; DNA sequencing; Epstein-Barr virus; Epstein-Barr virus diseases; Epstein-Barr Virus Infections - complications; Epstein-Barr Virus Infections - virology; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic Variation; Hematology; Herpesvirus 4, Human - isolation & purification; Histology; Humans; Immune checkpoint; Immunity; Immunotherapy; Intensive; Internal Medicine; Intracellular signalling; Lesions; Leukemia; Ligands; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, Extranodal NK-T-Cell - genetics; Lymphoma, Extranodal NK-T-Cell - immunology; Lymphoma, Extranodal NK-T-Cell - virology; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - immunology; Lymphoma, Large B-Cell, Diffuse - virology; Lymphoma, T-Cell, Peripheral - genetics; Lymphoma, T-Cell, Peripheral - immunology; Lymphoma, T-Cell, Peripheral - virology; Lymphomas; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mutation; MyD88 protein; Next-generation sequencing; Nucleotide sequencing; Oncology; PD-L1 protein; Programmed Cell Death 1 Ligand 2 Protein - genetics; Risk factors; T-cell lymphoma; Viruses
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-019-0380-5

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.