abstract
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 regions across cancers with
putative biological and clinical consequences. We noted a strong
correlation between PD-L1 CNAs and
mRNA expression levels for most cancers and found tumors with PD-L1
gains to harbor significantly higher mutational loads 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.
