The KDR (VEGFR-2) Genetic Polymorphism Q472H and c-KIT Polymorphism M541L Are Associated With More Aggressive Behaviour in Astrocytic Gliomas

Abstract

Background/Aim: Better diagnostic and prognostic markers are required for a more accurate diagnosis and an earlier detection of glioma progression and for suggesting better treatment strategies. This retrospective study aimed to identify actionable gene variants to define potential markers of clinical significance. Materials and Methods: 56 glioblastomas (GBM) and 44 grade 2-3 astrocytomas were profiled with next generation sequencing (NGS) as part of routine diagnostic workup and bioinformatics analysis was used for the identification of variants. CD34 immunohistochemistry (IHC) was used to measure microvessel density (MVD) and Log-rank test to compare survival and progression in the presence or absence of these variants. Results: Bioinformatic analysis highlighted frequently occurring variants in genes involved in angiogenesis regulation (KDR, KIT, TP53 and PIK3CA), with the most common ones being KDR (rs1870377) and KIT (rs3822214). The KDR variant was associated with increased MVD and shorter survival in GBM. We did not observe any correlation between the KIT variant and MVD; however, there was an association with tumour grade. Conclusion: This study highlights the role of single-nucleotide variants (SNVs) that may be considered non-pathogenic and suggests the prognostic significance for survival of KIT rs3822214 and KDR rs1870377 and potential importance in planning new treatment strategies for gliomas.

c-Kit M541L variant is related to ineffective hemopoiesis predisposing to clonal evolution in 3D in vitro biomimetic co-culture model of bone marrow niche

“…Conversely, loss-of-function mutations have been poorly described and found in benign conditions, such as piebaldism, an inherited disease with patches of white skin or hair [ 57 ]. The Met541Leu variant located on exon 10 of c-Kit (corresponding to the transmembrane domain), also found in our haploidentical donor, have been described in a case series of chronic myeloid leukemia Japanese patients, and in aggressive astrocytic gliomas [ 58 , 59 ]. However, others have reported a similar frequency (8.1%) of this Met541Leu variant in normal population; therefore, clinical significance of this missense mutation is still unclear [ 60 ].…”

Tumor location matters, next generation sequencing mutation profiling of left-sided, rectal, and right-sided colorectal tumors in 552 patients

“…Additionally, cell lines derived from patients with the variant show increased proliferation and a greater invasive potential and are more sensitive to targeted VEGFR2 inhibition than those without the variant 38 . Co-occurrence of the KDR p.(Gln472His) and KIT p.(Met541Leu) variants is associated with aggressive forms of glioblastoma multiforme 39 . The KDR p.(Gln472His) variant is listed as 'likely oncogenic' in the OncoKB database ( https://www.oncokb.org/gene/KDR ).…”

Pan-Cancer Analysis Identified CD93 as a Valuable Biomarker for Predicting Patient Prognosis and Immunotherapy Response

“…Meanwhile, CD93 and KDR have shown a significant co-expression relationship in various tumors. Current evidence shows that the expression of p-KDR is closely related to the density of vasculogenic mimicry (VM) in GBM and adverse clinical outcomes ( Zaman et al, 2020 ).…”