Abstract
Understanding human genome alterations is necessary to optimize genome-based cancer therapeutics. However, some newly discovered mutations remain as variants of unknown significance (VUS). Here, the mutation c.1403A > G in exon 10 of the platelet-derived growth factor receptor-alpha (PDGFRA) gene, a VUS found in adult glioblastoma multiforme (GBM), was introduced in human embryonal kidney 293 T (HEK293T) cells using genome editing to investigate its potential oncogenic functions. Genome editing was performed using CRISPR/Cas9; the proliferation, drug sensitivity, and carcinogenic potential of genome-edited cells were investigated. We also investigated the mechanism underlying the observed phenotypes. Three GBM patients carrying the c.1403A > G mutation were studied to validate the in vitro results. The c.1403A > G mutation led to a splice variant (p.K455_N468delinsN) because of the generation of a 3’-acceptor splice site in exon 10. PDGFRA-mutated HEK293T cells exhibited a higher proliferative activity via PDGFRα and the cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 signaling pathway in a ligand-independent manner. They showed higher sensitivity to multi-kinase, receptor tyrosine kinase, and CDK4/CDK6 inhibitors. Of the three GBM patients studied, two harbored the p.K455_N468delinsN splice variant. The splicing mutation c.1403A > G in PDGFRA is oncogenic in nature. Kinase inhibitors targeting PDGFRα and CDK4/CDK6 signaling should be evaluated for treating GBM patients harboring this mutation.
Highlights
The development of new technologies, such as next-generation sequencing (NGS), has led to the accumulation of annotation data related to cancer g enomics[1–4]
We recently reported the existence of a subgroup of patients harboring mutations in the platelet-derived growth factor receptor-alpha (PDGFRA) gene6; 11 out of 64 glioblastoma multiforme (GBM) cases (17%) harbored wild-type IDH1 and showed no 1p19q co-deletion (Table S1)
We clearly show that the c.1403A > G mutation produces a novel splicing site, resulting in the in-frame internal deletion and subsequent PDGFRA splicing variant p.K455_N468delinsN
Summary
The development of new technologies, such as next-generation sequencing (NGS), has led to the accumulation of annotation data related to cancer g enomics[1–4]. We reported a rare variant of the gene encoding the platelet-derived growth factor receptor-alpha (PDGFRA) using NGS in IDH1 wild-type glioblastoma multiforme (GBM)[6]. This VUS is a member of a possible Japanese (or Asian) genotype group manifested by PDGFRA gene amplification and mutation, but without TERT promoter mutations. As the availability of molecularly targeted drugs for brain tumors is limited, the elucidation of oncogenic functions of VUS, including in the PDGFRA gene, is essential for the development of new drugs.
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