Analysis of copy number loss of the ErbB4 receptor tyrosine kinase in glioblastoma

Abstract

Current treatments for glioblastoma multiforme (GBM)—an aggressive form of brain cancer—are minimally effective and yield a median survival of 14.6 months and a two-year survival rate of 30%. Given the severity of GBM and the limitations of its treatment, there is a need for the discovery of novel drug targets for GBM and more personalized treatment approaches based on the characteristics of an individual’s tumor. Most receptor tyrosine kinases—such as EGFR—act as oncogenes, but publicly available data from the Cancer Cell Line Encyclopedia (CCLE) indicates copy number loss in the ERBB4 RTK gene across dozens of GBM cell lines, suggesting a potential tumor suppressor role. This loss is mutually exclusive with loss of its cognate ligand NRG1 in CCLE as well, more strongly suggesting a functional role. The availability of higher resolution copy number data from clinical GBM patients in The Cancer Genome Atlas (TCGA) revealed that a region in Intron 1 of the ERBB4 gene was deleted in 69.1% of tumor samples harboring ERBB4 copy number loss; however, it was also found to be deleted in the matched normal tissue samples from these GBM patients (n = 81). Using the DECIPHER Genome Browser, we also discovered that this mutation occurs at approximately the same frequency in the general population as it does in the disease population. We conclude from these results that this loss in Intron 1 of the ERBB4 gene is neither a de novo driver mutation nor a predisposing factor to GBM, despite the indications from CCLE. A biological role of this significantly occurring genetic alteration is still unknown. While this is a negative result, the broader conclusion is that while copy number data from large cell line-based data repositories may yield compelling hypotheses, careful follow up with higher resolution copy number assays, patient data, and general population analyses are essential to codify initial hypotheses prior to investing experimental resources.

A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors

“…Glioblastoma multiforme (GBM) is the most prevalent central nervous system cancer, which is the most common, severe, and difficult to treat [ 88 ]. Studies of HER family members show that HER4 is one of the most common proteins in GBM [ 89 ].…”

“…CCLE data suggests a role of HER4 as a tumor suppressor, by showing copy number loss of HER4 gene through several cell lines of GBM. However, the same variants have been shown to occur at about the same frequencies in the general population [ 88 ]. Though GBM has an average low level of HER4 expression, in 11 % of cases, high pHER4 expression was found to be present and associated with reduced survival than no pHER4 expression [ 90 ].…”

Glioblastoma: two immune subtypes under the surface of the cold tumor

“…Although the mutation rate was low, most of these genes had copy number loss. It has been demonstrated that gene copy number loss is linked to tumorigenesis [ 12 , 13 ]; for example, the loss of ErbB4 receptor tyrosine kinase is linked to the development of glioblastoma [ 14 ]. Thus, immune gene copy number loss may play a role in the development of glioblastoma.…”

Phytanoyl-CoA 2-Hydroxylase-Interacting Protein-Like Gene Is a Therapeutic Target Gene for Glioblastoma Multiforme

“…The mechanism is not clear. It contains epigenetic alterations [14,15], mutation [16], copy numbers variations [17], DNA damage [18], microenvironment [19], and extracellular matrix [20]. The downregulated DEGs were significantly enriched in the extracellular matrix and the KEGG enrichment suggests that downregulated DEGs were significantly enriched in the TNF signaling pathway and the IL-17 signaling pathway.…”