Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) - associations with gene expression, mutational load, and survival
| Autor: | Silvia Darb-Esfahani, Jochen K. Lennerz, Michael Bockmayr, Carsten Denkert, A. John Iafrate, Stefan Fröhling, Manfred Dietel, Jonas Leichsenring, Nicole Pfarr, Frederick Klauschen, Jan Budczies, Stefan Gröschel, Peter Schirmacher, Albrecht Stenzinger, Wilko Weichert, Maristela L. Onozato |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Regulation of gene expression Cancer Research Bladder cancer Melanoma medicine.medical_treatment Head and neck cancer Chromosome 9 Immunotherapy Biology medicine.disease Bioinformatics 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis PD-L1 Genetics medicine Cancer research biology.protein Ovarian cancer |
| Zdroj: | Genes, Chromosomes and Cancer. 55:626-639 |
| ISSN: | 1045-2257 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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