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Molecular Landscape for Malignant Transformation in Diffuse Astrocytoma.

ABSTRACT: Background Malignant transformation (MT) of low-grade gliomas changes dramatically the natural history to poor prognosis. Currently, factors associated with MT of gliomas have been inconclusive, in particular, diffuse astrocytoma (DA). Objective The present study aimed to explore the molecular abnormalities related to MT in the same patients with different MT stages. Methods Twelve specimens from five DA patients with MT were genotyped using next-generation sequencing (NGS) to identify somatic variants in different stages of MT. We used cross-tabulated categorical biological variables and compared the mean of continuous variables to assess for association with MT. Results Ten samples succussed to perform NGS from one male and four females, with ages ranging from 28 to 58 years. The extent of resection was commonly a partial resection following postoperative temozolomide with radiotherapy in 25% of cases. For molecular findings, poly-T-nucleotide insertion in isocitrate dehydrogenase 1 (IDH1) was significantly related to MT as a dose-response relationship (Mann-Whitney's U test, p = 0.02). Also, mutations of KMT2C and GGT1 were frequently found in the present cohort, but those did not significantly differ between the two groups using Fisher's exact test. Conclusion In summary, we identified a novel relationship between poly-T insertion polymorphisms that established the pathogenesis of MT in DA. A further study should be performed to confirm the molecular alteration with more patients.

SUBMITTER: Tunthanathip T

PROVIDER: S-EPMC8378925 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Malignant astrocytoma (MA) is the most common and severe type of brain tumor. A greater understanding of the underlying mechanisms responsible for the development of MA would be beneficial for the development of targeted molecular therapies. In the present study, the upregulated differentially expressed genes (DEGs) in MA were obtained from the Gene Expression Omnibus database using R/Bioconductor software. DEGs in different World Health Organization classifications were compared using the Venny tool and 15 genes, including collagen type I ?1 chain (COL1A1) and laminin subunit ?1 (LAMC1), were revealed to be involved in the malignant progression of MA. In addition, the upregulated DEGs in MA were evaluated using functional annotations of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes with the Database for Annotation, Visualization, and Integrated Discovery tool. The results indicated that invasion?associated enrichment was observed in 'extracellular matrix' (ECM), 'cell adhesion' and 'phosphoinositide 3?kinase?protein kinase B signaling pathway'. Subsequently, the analysis of the protein?protein interactions was performed using STRING and Cytoscape software, which revealed that the ECM component was the invasion?associated module and its corresponding genes included COL1A1, LAMC1 and fibronectin 1. Finally, survival Kaplan?Meier estimate was conducted using cBioportal online, which demonstrated that COL1A1 expression affected the survival of and recurrence in patients with MA. Moreover, the results of in vitro Transwell assay and western blot analysis revealed that the depleted levels of COL1A1 also decreased the expression of several proteins associated with cell invasion, including phosphorylated?signal transducer and activator of transcription 3, matrix metalloproteinase (MMP)?2, MMP?9 and nuclear factor??B. On the whole, the present study identified the invasion?related target genes and the associated potential pathways in MA. The results indicated that COL1A1 may be a candidate biomarker for the prognosis and treatment of MA.

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Molecular Landscape for Malignant Transformation in Diffuse Astrocytoma.

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