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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
Author(s) -
Budczies Jan,
Bockmayr Michael,
Denkert Carsten,
Klauschen Frederick,
Gröschel Stefan,
DarbEsfahani Silvia,
Pfarr Nicole,
Leichsenring Jonas,
Onozato Maristela L.,
Lennerz Jochen K.,
Dietel Manfred,
Fröhling Stefan,
Schirmacher Peter,
Iafrate A. John,
Weichert Wilko,
Stenzinger Albrecht
Publication year - 2016
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22365
Subject(s) - cancer , copy number variation , biology , pd l1 , cancer research , melanoma , colorectal cancer , cervical cancer , gene , immunotherapy , oncology , medicine , genetics , genome
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.