Frequent genetic alterations in immune checkpoint-related genes in intravascular large B-cell lymphoma

被引：77

作者：

Shimada, Kazuyuki ^{[1
,2
]}

Yoshida, Kenichi ^{[3
]}

Suzuki, Yasuhiro ^{[1
,4
]}

Iriyama, Chisako ^{[1
,5
]}

Inoue, Yoshikage ^{[3
,6
]}

Sanada, Masashi ^{[7
]}

Kataoka, Keisuke ^{[3
,8
]}

Yuge, Masaaki ^{[9
]}

Takagi, Yusuke ^{[10
,11
]}

Kusumoto, Shigeru ^{[12
]}

Masaki, Yasufumi ^{[13
]}

Ito, Takahiko ^{[14
]}

Inagaki, Yuichiro ^{[15
]}

Okamoto, Akinao ^{[5
]}

Kuwatsuka, Yachiyo ^{[16
]}

Nakatochi, Masahiro ^{[17
]}

Shimada, Satoko ^{[18
]}

Miyoshi, Hiroaki ^{[19
]}

Shiraishi, Yuichi ^{[20
]}

Chiba, Kenichi ^{[20
]}

Tanaka, Hiroko ^{[21
]}

Miyano, Satoru ^{[21
,22
]}

Shiozawa, Yusuke ^{[23
]}

Nannya, Yasuhito ^{[3
]}

Okabe, Asako ^{[24
]}

Kohno, Kei ^{[18
,19
]}

Atsuta, Yoshiko ^{[25
]}

Ohshima, Koichi ^{[19
]}

Nakamura, Shigeo ^{[18
]}

Ogawa, Seishi ^{[3
,26
,27
]}

Tomita, Akihiro ^{[1
,5
]}

Kiyoi, Hitoshi ^{[1
]}

机构：

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

[2] Nagoya Univ, Inst Adv Res, Nagoya, Aichi, Japan

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

[4] Natl Hosp Org Nagoya Med Ctr, Dept Hematol, Nagoya, Aichi, Japan

[5] Fujita Hlth Univ, Sch Med, Dept Hematol, 1-98 Dengakugakubo,Kutsukake Cho, Toyoake, Aichi 4701192, Japan

[6] Kyoto Univ, Grad Sch Med, Dept Surg, Kyoto, Japan

[7] Natl Hosp Org Nagoya Med Ctr, Clin Res Ctr, Nagoya, Aichi, Japan

[8] Natl Canc Ctr, Div Mol Oncol, Tokyo, Japan

[9] Ichinomiya Municipal Hosp, Dept Hematol, Ichinomiya, Japan

[10] Toyota Kosei Hosp, Dept Hematol, Toyota, Japan

[11] Ogaki Municipal Hosp, Dept Hematol, Ogaki, Japan

[12] Nagoya City Univ, Grad Sch Med Sci, Dept Hematol & Oncol, Nagoya, Aichi, Japan

[13] Kanazawa Med Univ, Dept Hematol & Immunol, Uchinada, Ishikawa, Japan

[14] Japan Community Hlth Care Org JCHO Kani Tono Hosp, Dept Hematol, Kani, Japan

[15] Anjo Kosei Hosp, Dept Hematol & Oncol, Anjo, Aichi, Japan

[16] Nagoya Univ Hosp, Dept Adv Med, Nagoya, Aichi, Japan

[17] Nagoya Univ, Grad Sch Med, Dept Integrated Hlth Sci, Publ Hlth Informat Unit, Nagoya, Aichi, Japan

[18] Nagoya Univ Hosp, Dept Pathol & Lab Med, Nagoya, Aichi, Japan

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

[20] Natl Canc Ctr, Div Cellular Signaling, Tokyo, Japan

[21] Univ Tokyo, Lab DNA Informat Anal, Tokyo, Japan

[22] Univ Tokyo, Human Genome Ctr, Inst Med Sci, Lab Sequence Anal, Tokyo, Japan

[23] Univ Tokyo, Grad Sch Med, Dept Pediat, Tokyo, Japan

[24] Fujita Hlth Univ, Sch Med, Dept Pathol, Toyoake, Aichi, Japan

[25] Japanese Data Ctr Hematopoiet Cell Transplantat, Nagoya, Aichi, Japan

[26] Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden

[27] Kyoto Univ, World Premier Int Res Ctr Initiat, Inst Adv Study Human Biol WPI ASHBI, Kyoto, Japan

来源：

BLOOD | 2021年 / 137卷 / 11期

基金：

日本学术振兴会;

关键词：

D O I：

10.1182/blood.2020007245

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Intravascular large B-cell lymphoma (IVLBCL) is a unique type of extranodal lymphoma characterized by selective growth of tumor cells in small vessels without lymphadenopathy. Greater understanding of the molecular pathogenesis of IVLBCL is hampered by the paucity of lymphoma cells in biopsy specimens, creating a limitation in obtaining sufficient tumor materials. To uncover the genetic landscape of IVLBCL, we performed whole-exome sequencing (WES) of 21 patients with IVLBCL using plasma-derived cell-free DNA (cfDNA) (n=18), patient-derived xenograft tumors (n=4), and tumor DNA from bone marrow (BM) mononuclear cells (n=2). The concentration of cfDNA in IVLBCL was significantly higher than that in diffuse large B-cell lymphoma (DLBCL) (P<.0001) and healthy donors (P=.0053), allowing us to perform WES; most mutations detected in BM tumor DNA were successfully captured in cfDNA and xenograft. IVLBCL showed a high frequency of genetic lesions characteristic of activated B-cell-type DLBCL, with the former showing conspicuously higher frequencies (compared with nodal DLBCL) of mutations in MYD88 (57%), CD79B (67%), SETD1B (57%), and HLA-B (57%). We also found that 8 IVLBCL (38%) harbored re-arrangements of programmed cell death 1 ligand 1 and 2 (PD-L1/PD-L2) involving the 39 untranslated region; such rearrangements are implicated in immune evasion via PD-L1/PD-L2 overexpression. Our data demonstrate the utility of cfDNA and imply important roles for immune evasion in IVLBCL pathogenesis and PD-1/PD-L1/PD-L2 blockade in therapeutics for IVLBCL.

引用

页码：1491 / 1502

页数：12

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