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

被引：123

作者：

Kataoka, Keisuke ^{[1
,2
]}

Miyoshi, Hiroaki ^{[3
]}

Sakata, Seiji ^{[4
]}

Dobashi, Akito ^{[4
]}

Couronne, Lucile ^{[5
,6
,7
,8
]}

Kogure, Yasunori ^{[13
]}

Sato, Yasuharu ^{[9
,10
]}

Nishida, Kenji ^{[9
]}

Gion, Yuka ^{[9
]}

Shiraishi, Yuichi ^{[11
]}

Tanaka, Hiroko ^{[11
]}

Chiba, Kenichi ^{[11
]}

Watatani, Yosaku ^{[1
]}

Kakiuchi, Nobuyuki ^{[1
]}

Shiozawa, Yusuke ^{[1
]}

Yoshizato, Tetsuichi ^{[1
]}

Yoshida, Kenichi ^{[1
]}

Makishima, Hideki ^{[1
]}

Sanada, Masashi ^{[12
]}

Onozawa, Masahiro ^{[13
]}

Teshima, Takanori ^{[13
]}

Yoshiki, Yumiko ^{[14
]}

Ishida, Tadao ^{[14
]}

Suzuki, Kenshi ^{[14
]}

Shimada, Kazuyuki ^{[15
]}

Tomita, Akihiro ^{[15
]}

Kato, Motohiro ^{[16
]}

Ota, Yasunori ^{[17
]}

Izutsu, Koji ^{[18
]}

Demachi-Okamura, Ayako ^{[19
]}

Akatsuka, Yoshiki ^{[19
,20
]}

Miyano, Satoru ^{[11
]}

Yoshino, Tadashi ^{[9
]}

Gaulard, Philippe ^{[21
,22
,23
]}

Hermine, Olivier ^{[5
,6
,7
,8
]}

Takeuchi, Kengo ^{[4
]}

Ohshima, Koichi ^{[3
]}

Ogawa, Seishi ^{[1
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Kyoto, Japan

[2] Natl Canc Ctr, Div Mol Oncol, Res Inst, Tokyo, Japan

[3] Kurume Univ, Dept Pathol, Sch Med, Kurume, Fukuoka, Japan

[4] Japanese Fdn Canc Res, Inst Canc, Pathol Project Mol Targets, Tokyo, Japan

[5] Hop Necker Enfants Malad, AP HP, Dept Hematol, Paris, France

[6] INSERM, UMR 1163, Paris, France

[7] CNRS, ERL 8254, Lab Cellular & Mol Mech Hematol Disorders & Thera, Imagine Inst, Paris, France

[8] Paris Descartes Sorbonne Paris Cite Univ, Paris, France

[9] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pathol, Okayama, Japan

[10] Okayama Univ, Div Pathophysiol, Grad Sch Hlth Sci, Okayama, Japan

[11] Univ Tokyo, Lab DNA Informat Anal, Ctr Human Genome, Inst Med Sci, Tokyo, Japan

[12] Nagoya Med Ctr, Dept Adv Diag, Clin Res Ctr, Nagoya, Aichi, Japan

[13] Hokkaido Univ, Dept Hematol, Fac Med, Sapporo, Hokkaido, Japan

[14] Japanese Red Cross Med Ctr, Dept Hematol, Tokyo, Japan

[15] Nagoya Univ, Dept Hematol & Oncol, Grad Sch Med, Nagoya, Aichi, Japan

[16] Natl Ctr Child Hlth & Dev, Dept Pediat Hematol & Oncol Res, Tokyo, Japan

[17] Toranomon Gen Hosp, Dept Pathol, Tokyo, Japan

[18] Toranomon Gen Hosp, Dept Hematol, Tokyo, Japan

[19] Aichi Canc Ctr, Div Immunol, Res Inst, Nagoya, Aichi, Japan

[20] Fujita Hlth Univ, Dept Hematol, Sch Med, Toyoake, Aichi, Japan

[21] Henri Mondor Hosp, AP HP, Dept Pathol, Creteil, France

[22] Inst Mondor Rech Biomed, INSERM, U955, Equipe 9, Creteil, France

[23] Paris Est Univ, Creteil, France

来源：

LEUKEMIA | 2019年 / 33卷 / 07期

关键词：

B-CELL LYMPHOMA; CLASSICAL HODGKIN LYMPHOMA; IMMUNE CHECKPOINT BLOCKADE; GENETIC ALTERATIONS; SOMATIC MUTATIONS; RECURRENT; PD-L1; REARRANGEMENTS; PEMBROLIZUMAB; EXPRESSION;

D O I：

10.1038/s41375-019-0380-5

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1687 / 1699

页数：13

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