Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) - associations with gene expression, mutational load, and survival.
Inhibition of the PD-L1 (CD274) - PD-1 axis has emerged as a powerful cancer therapy that prevents evasion of tumor cells from the immune system. While immunohistochemical detection of PD-L1 was introduced as a predictive biomarker with variable power, much less is known about copy number alterations (CNA) affecting PD-L1 and their associations with expression levels, mutational load, and survival. To gain insight, we employed The Cancer Genome Atlas (TCGA) datasets to comprehensively analyze 22 major cancer types for PD-L1 CNAs. We observed a diverse landscape of PD-L1 CNAs, which affected focal regions, chromosome 9p or the entire chromosome 9. Deletions of PD-L1 were more frequent than gains (31% vs. 12%) with deletions being most prevalent in melanoma and non-small cell lung cancer. Copy number gains most frequently occurred in ovarian cancer, head and neck cancer, bladder cancer, cervical and endocervical cancer, sarcomas, and colorectal cancers. Fine-mapping of the genetic architecture revealed specific recurrently amplified and deleted core regions across cancers with putative biological and clinical consequences. PD-L1 CNAs correlated significantly with PD-L1 mRNA expression changes in many cancer types, and tumors with PD-L1 gains harbored significantly higher mutational load compared to non-amplified cases (median: 78 non-synonymous mutations vs. 40, P = 7.1e-69). Moreover, we observed that, in general, both PD-L1 amplifications and deletions were associated with dismal prognosis. In conclusion, PD-L1 CNAs, in particular PD-L1 copy number gains, represent frequent genetic alterations across many cancers, which influence PD-L1 expression levels, are associated with higher mutational loads, and may be exploitable as predictive biomarker for immunotherapy regimens. © 2016 Wiley Periodicals, Inc.
Institute of Pathology, Charité University Hospital, Berlin, Germany.|German Cancer Consortium (DKTK), Germany.
Jan
J
Budczies
Institute of Pathology, Charité University Hospital, Berlin, Germany.
Michael
M
Bockmayr
Institute of Pathology, Charité University Hospital, Berlin, Germany.|German Cancer Consortium (DKTK), Germany.
Carsten
C
Denkert
Institute of Pathology, Charité University Hospital, Berlin, Germany.
Frederick
F
Klauschen
German Cancer Consortium (DKTK), Germany.|Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
Stefan
S
Gröschel
Institute of Pathology, Charité University Hospital, Berlin, Germany.
Silvia
S
Darb-Esfahani
Institute of Pathology, Technical University Munich, Germany.
Nicole
N
Pfarr
Institute of Pathology, University Hospital Heidelberg, Germany.
Jonas
J
Leichsenring
Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital, Harvard Medical School, MA.
Maristela L
ML
Onozato
Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital, Harvard Medical School, MA.
Jochen K
JK
Lennerz
Institute of Pathology, Charité University Hospital, Berlin, Germany.|German Cancer Consortium (DKTK), Germany.
Manfred
M
Dietel
German Cancer Consortium (DKTK), Germany.|Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
Stefan
S
Fröhling
German Cancer Consortium (DKTK), Germany.|Institute of Pathology, University Hospital Heidelberg, Germany.
Peter
P
Schirmacher
Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital, Harvard Medical School, MA.
A John
AJ
Iafrate
German Cancer Consortium (DKTK), Germany.|Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital, Harvard Medical School, MA.
Wilko
W
Weichert
Institute of Pathology, University Hospital Heidelberg, Germany.|Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital, Harvard Medical School, MA.|National Center for Tumor Diseases (NCT), Heidelberg, Germany.
Albrecht
A
Stenzinger
D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics
D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor