Pan‐cancer analysis of copy number changes in programmed death‐ligand 1 (PD‐L1, CD274) – associations with gene expression, mutational load, and survival

Abstract

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.

Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification

“…Although future studies are needed to further establish robust and reliable determinants of response to ICI (Carbognin et al 2015; Patel and Kurzrock 2015), PDL1 amplification might serve as a rapidly available and inexpensive surrogate marker across histologic entities, as supported by the striking therapeutic activity of PD1 blockade in TNBC (this study) and refractory classical Hodgkin lymphoma (Ansell et al 2015; Roemer et al 2016) characterized by Chromosome 9p24.1 gain. In a recent pan-cancer analysis, PDL1 gains were shown to occur in many cancer types and to result in PDL1 mRNA overexpression in some tumors (Budczies et al 2016). Moreover, a PDL1 core amplification region of 7.8 Mb on Chromosome 9p that extended to the telomere was identified, consistent with the finding in this report.…”

“…Breast cancer data sets (study brca_tcga_pub2015) including data on DNA copy number status (GISTIC) and mRNA expression (RNA Seq V2 RSEM) of PDL1 were retrieved from the cBioPortal for Cancer Genomics () and analyzed as described previously (Budczies et al 2016). Immunohistochemistry data for ER, PR, and HER2 as well as FISH data for HER2 were retrieved from the TCGA data portal ().…”

PD-L1 status in refractory lymphomas

“…Genomic rearrangements of PD-L1 have also been described in primary mediastinal large Bcell lymphomas [22]. A recent comprehensive survey of Budczies et al [15] revealed frequent PD-L1 copy number variations (gains and amplifications [12%], deletions [31%]) across different cancer subtypes with direct impact on its protein and mRNA expression.…”

Molecular Mechanisms of Carcinogenesis of Epithelial Ovarian Cancers

“…Přítomnost MSI je také významným prediktorem při terapii kolorektálních karcinomů pomocí checkpoint inhibitorů, terapeutických protilátek blokujících povrchové molekuly PD-1 a PD-L1 [29][30][31]. Vzhledem k tomu, že použití checkpoint inhibitorů přineslo v posledních letech významný posun v léčbě celé řady nádorových onemocnění, zvažuje se jejich využití i pro terapii ovariálních karcinomů [32,33]. Detekce poruch MMR a MSI by se tak v budoucnu mohla stát jedním z důležitých prediktivních markerů pro terapii využívající checkpoint inhibitory.…”