Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) - associations with gene expression, mutational load, and survival
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Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) - associations with gene expression, mutational load, and survival. / Budczies, Jan; Bockmayr, Michael; Denkert, Carsten; Klauschen, Frederick; Gröschel, Stefan; Darb-Esfahani, Silvia; Pfarr, Nicole; Leichsenring, Jonas; Onozato, Maristela L; Lennerz, Jochen K; Dietel, Manfred; Fröhling, Stefan; Schirmacher, Peter; Iafrate, A John; Weichert, Wilko; Stenzinger, Albrecht.
in: GENE CHROMOSOME CANC, Jahrgang 55, Nr. 8, 08.2016, S. 626-39.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) - associations with gene expression, mutational load, and survival
AU - Budczies, Jan
AU - Bockmayr, Michael
AU - Denkert, Carsten
AU - Klauschen, Frederick
AU - Gröschel, Stefan
AU - Darb-Esfahani, Silvia
AU - Pfarr, Nicole
AU - Leichsenring, Jonas
AU - Onozato, Maristela L
AU - Lennerz, Jochen K
AU - Dietel, Manfred
AU - Fröhling, Stefan
AU - Schirmacher, Peter
AU - Iafrate, A John
AU - Weichert, Wilko
AU - Stenzinger, Albrecht
N1 - © 2016 Wiley Periodicals, Inc.
PY - 2016/8
Y1 - 2016/8
N2 - 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.
AB - 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.
KW - Antigens, CD274
KW - Biomarkers, Tumor
KW - DNA Copy Number Variations
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Immunotherapy
KW - Mutation
KW - Neoplasms
KW - Programmed Cell Death 1 Receptor
KW - Journal Article
U2 - 10.1002/gcc.22365
DO - 10.1002/gcc.22365
M3 - SCORING: Journal article
C2 - 27106868
VL - 55
SP - 626
EP - 639
JO - GENE CHROMOSOME CANC
JF - GENE CHROMOSOME CANC
SN - 1045-2257
IS - 8
ER -