title: Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas.
abstract: Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive types of B-cell lymphoma. Deregulation of proto-oncogene expression after a translocation, most notably to the immunoglobulin heavy-chain locus (IGH), is one of the hallmarks of DLBCL. Using whole-genome sequencing analysis, we have identified the PD-L1/PD-L2 locus as a recurrent translocation partner for IGH in DLBCL. PIM1 and TP63 were also identified as novel translocation partners for PD-L1/PD-L2 Fluorescence in situ hybridization was furthermore used to rapidly screen an expanded DLBCL cohort. Collectively, a subset of samples was found to be affected by gains (12%), amplifications (3%), and translocations (4%) of the PD-L1/PD-L2 locus. RNA sequencing data coupled with immunohistochemistry revealed that these cytogenetic alterations correlated with increased expression of PD-L1 but not of PD-L2 Moreover, cytogenetic alterations affecting the PD-L1/PD-L2 locus were more frequently observed in the non-germinal center B cell-like (non-GCB) subtype of DLBCL. These findings demonstrate the genetic basis of PD-L1 overexpression in DLBCL and suggest that treatments targeting the PD-1-PD-L1/PD-L2 axis might benefit DLBCL patients, especially those belonging to the more aggressive non-GCB subtype.
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden;
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Georgiou
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden; BGI-Shenzhen, Shenzhen, China;
authors.forename: Longyun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden;
authors.forename: Mattias
authors.initials: M
authors.lastname: Berglund
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden;
authors.forename: Weicheng
authors.initials: W
authors.lastname: Ren
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Noel F C C
authors.initials: NF
authors.lastname: de Miranda
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, and Abel Salazar Biomedical Sciences Institute, Porto University, Porto, Portugal;
authors.forename: Susana
authors.initials: S
authors.lastname: Lisboa
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Marco
authors.initials: M
authors.lastname: Fangazio
authors.affiliation: BGI-Shenzhen, Shenzhen, China;
authors.forename: Shida
authors.initials: S
authors.lastname: Zhu
authors.affiliation: BGI-Shenzhen, Shenzhen, China;
authors.forename: Yong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: BGI-Shenzhen, Shenzhen, China;
authors.forename: Kui
authors.initials: K
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Oncology in South China and Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China;
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Fang
authors.affiliation: Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China;
authors.forename: Xianhuo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China;
authors.forename: Bin
authors.initials: B
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Oncology in South China and Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China;
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncology in South China and Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China;
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY;
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden; and.
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbecklaboratoriet, Uppsala University, Uppsala, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Sundström
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbecklaboratoriet, Uppsala University, Uppsala, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Enblad
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.affiliation: Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China;
authors.forename: Huilai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, and Abel Salazar Biomedical Sciences Institute, Porto University, Porto, Portugal;
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.affiliation: State Key Laboratory of Oncology in South China and Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China;
authors.forename: Roujun
authors.initials: R
authors.lastname: Peng
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden;
authors.forename: Qiang
authors.identifier: 0000-0003-1990-8804
authors.initials: Q
authors.lastname: Pan-Hammarström
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D060890:B7-H1 Antigen / Q000235:genetics*; D015331:Cohort Studies; D020732:Cytogenetic Analysis; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D050438:Genes, Immunoglobulin Heavy Chain; D055106:Genome-Wide Association Study; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D014178:Translocation, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas