Copy number variations in critical cell-signalling genes with potential targeted therapeutic application

Abstract

Abstract Background Brain tumours are among “hard-to treat” world malignancy with the median survival time of 15 months for the most aggressive form - Glioblastoma multiforme (GBM). It is extremely complex and heterogeneous brain cancer, characterized by rapid progression, infiltration and therapeutic resistance. Currently, many trials for target therapy are focused on understanding the molecular heterogeneity of GBM and designing molecules that inhibit most common genetic alterations. Methods In the present study, somatic copy number variations (CNVs) in critical signalling genes suitable for future target therapy are examined among Bulgarian patients. Fresh brain biopsies were collected from patients with primary and secondary GBM. Genomic DNA was isolated and CNVs were analysed by Multiplex ligation – dependent probe amplification (MLPA). Results CDKN2A deletion is the most frequent genetic alteration (78%) among Bulgarian patients with GBM. The loss of this gene is a progression-associated genetic marker. Nearly 60% of GBM patients showed EGFR amplification. It is a prognostic and predictive marker and some patients with this aberration are suggested to respond better to EGFR inhibitors in combination therapy. PTEN deletion is another common event with the incidence rate of 33% and its loss corelates with the choice of mTOR and MEK inhibitors, as well as, the resistance to some EGFR inhibitors. TP53 deletion was found in only 11% of the analysed patients which is a positive marker and the presence of wild-type TP53 is targeted by a MDM2 inhibitors. In addition, MDM2 amplification was observed in one patient and this event also serve as a potential target by MDM2 inhibitors.Amplification in PDGFRA is observed in one patient. Depending on the status of other receptor tyrosine kinases, it could be targeted by PDGFR inhibitor and is also suggested to be a poor prognostic marker. Conclusions Personalized treatment, customized for an individual patient genetics, has the potential to improve the therapy response. CNVs data could be useful for designing more effective personalized therapy. This is a small study on CNVs with potentially targeted therapeutic application in GBM for Bulgaria and recruitment of more patients is in progress. Legal entity responsible for the study The authors. Funding Medical University Sofia, Grant number D-127/2019. Disclosure All authors have declared no conflicts of interest.