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. 2024 May 27;16(5):e61165.
doi: 10.7759/cureus.61165. eCollection 2024 May.

Mutations in the TP53, VEGFA, and CTH Genes as Key Molecular Markers for the Diagnosis of Glioblastoma

Sardar S Khalil  1 , Abbas Salihi  2
Affiliations

Mutations in the TP53, VEGFA, and CTH Genes as Key Molecular Markers for the Diagnosis of Glioblastoma

Sardar S Khalil et al. Cureus. .

Abstract

Background Brain cancer, particularly glioblastoma (GBM), is a global health problem. Despite therapy advances, GBM patients have a poor prognosis. The progression and etiology of GBM may be linked to gene polymorphisms in the VEGFA, TP53, and CTH genes, among others. However, the genetic variations and their interaction in GBM are not fully understood. This study examines the effects of mutations in the VEGFA, TP53, and CTH genes on GBM. Methodology Tissue and blood samples were obtained for hematological, biochemical, and genetic analysis from 18 patients diagnosed with GBM as well as 28 healthy individuals. Standard methods were adopted to perform hematological and biochemical analyses, whereas mutational landscape and expression profiles were obtained from publicly accessible databases. Tissue samples were processed for genomic DNA extraction, and genotype determination was carried out through conventional polymerase chain reaction (PCR) and Sanger sequencing. Results The study involved 18 patients with grade IV GBM before treatment and 28 healthy individuals. The patients consisted of 11 men (61%) and seven females (39%), while healthy individuals included 14 (50%) males and 14 (50%) females. Sixty-seven percent of patients were under 50, 17% between 51 and 60, and 17% over 61, compared to healthy individuals who were 61% under 50, 7% between 51 and 60, and 32% over 60. GBM patients showed higher neutrophil and monocyte counts (median 81% (63.9, 83.5) and 4.2% (3.8-7.3)), respectively, and lower lymphocyte counts (median 13.4% (8.8, 28.40)) compared to controls. The median values of aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) showed no significant differences between the control and GBM groups. GBM patients had significantly higher median CRP levels of 2.55 (1.6, 98) than controls. Analysis of databases revealed a high prevalence of mutations in TP53, with splice region variants, missense variants, and intron variants being the most common. VEGFA and CTH also displayed mutations, primarily missense and intron variants. Gene expression analysis showed significantly higher levels of TP53 and VEGFA in GBM patients compared to controls. CTH expression also exhibited a slight increase in GBM patients. Sanger sequencing identified three mutations in the TP53 gene, including a novel mutation (11915C>A) not previously reported in external databases. Additionally, novel mutations were found in the VEGFA (841G>GA, 919T>TG) and CTH (28398A>AC, 28399A>AT) genes. Conclusions This study highlights the immune dysregulation, inflammation, and genetic variations in GBM. The findings emphasize the potential importance of the TP53, VEGFA, and CTH genes as targets for therapies and diagnostic biomarkers of GBM. Further study is necessary to comprehend these genetic variations' functional implications and their use in personalized GBM treatment.

Keywords: cth; gene mutation; glioblastoma; tp53; vegfa.

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Conflict of interest statement

Human subjects: Consent was obtained or waived by all participants in this study. Scientific Research Division's Research Ethics Committee of University of Duhok issued approval 15092021-9-13. All procedures contributing to this work met national and institutional human experimentation committees' ethical standards and the Declaration of Helsinki. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Figures

Figure 1
Figure 1. Comparison between the total number of WBCs, neutrophils, lymphocytes, and monocytes in healthy individuals and patients with GBM
(A) No significant changes were observed in the total number of WBCs. (B) The percentage of neutrophils was significantly increased in patients with GBM compared to healthy individuals. (C) The percentage of lymphocytes was significantly decreased in patients with GBM compared to healthy individuals. (D) The percentage of monocytes was significantly increased in patients with GBM compared to healthy individuals. The comparison was performed using an unpaired t-test. *p<0.05; **p<0.01 vs. healthy individuals; GBM: glioblastoma; WBC: white blood cell
Figure 2
Figure 2. Liver function markers and CRP levels in healthy individuals and GBM patients
No significant changes were observed in the AST (IU/L) (A), ALT (IU/L) (B), and ALP (IU/L) (C) in patients with GBM compared to healthy individuals. (D) The level of CRP (mg/L) was significantly increased in patients with GBM compared to healthy individuals. The comparison was performed using the Mann-Whitney test. **p<0.01 vs. healthy individuals; GBM: glioblastoma; ALT: alanine transaminase; AST: aspartate transaminase; ALP: alkaline phosphatase; CRP: C-reactive protein
Figure 3
Figure 3. TP53, VEGFA, and CTH gene expression in healthy individuals and patients with GBM retrieved from the GENT2 database.
The log2 expression values of TP53 (A), VEGFA (B), and CTH (C) genes were significantly increased in patients with GBM compared to healthy individuals. The comparison was performed using an unpaired t-test. **p<0.01; ****p<0.001 vs. healthy individuals; GBM: glioblastoma
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