Recurrence- and Malignant Progression-Associated Biomarkers in Low-Grade Gliomas and Their Roles in Immunotherapy

Abstract

Despite a generally better prognosis than high-grade glioma (HGG), recurrence and malignant progression are the main causes for the poor prognosis and difficulties in the treatment of low-grade glioma (LGG). It is of great importance to learn about the risk factors and underlying mechanisms of LGG recurrence and progression. In this study, the transcriptome characteristics of four groups, namely, normal brain tissue and recurrent LGG (rLGG), normal brain tissue and secondary glioblastoma (sGBM), primary LGG (pLGG) and rLGG, and pLGG and sGBM, were compared using Chinese Glioma Genome Atlas (CGGA) and Genotype-Tissue Expression Project (GTEx) databases. In this study, 296 downregulated and 396 upregulated differentially expressed genes (DEGs) with high consensus were screened out. Univariate Cox regression analysis of data from The Cancer Genome Atlas (TCGA) yielded 86 prognostically relevant DEGs; a prognostic prediction model based on five key genes (HOXA1, KIF18A, FAM133A, HGF, and MN1) was established using the least absolute shrinkage and selection operator (LASSO) regression dimensionality reduction and multivariate Cox regression analysis. LGG was divided into high- and low-risk groups using this prediction model. Gene Set Enrichment Analysis (GSEA) revealed that signaling pathway differences in the high- and low-risk groups were mainly seen in tumor immune regulation and DNA damage-related cell cycle checkpoints. Furthermore, the infiltration of immune cells in the high- and low-risk groups was analyzed, which indicated a stronger infiltration of immune cells in the high-risk group than that in the low-risk group, suggesting that an immune microenvironment more conducive to tumor growth emerged due to the interaction between tumor and immune cells. The tumor mutational burden and tumor methylation burden in the high- and low-risk groups were also analyzed, which indicated higher gene mutation burden and lower DNA methylation level in the high-risk group, suggesting that with the accumulation of genomic mutations and epigenetic changes, tumor cells continued to evolve and led to the progression of LGG to HGG. Finally, the value of potential therapeutic targets for the five key genes was analyzed, and findings demonstrated that KIF18A was the gene most likely to be a potential therapeutic target. In conclusion, the prediction model based on these five key genes can better identify the high- and low-risk groups of LGG and lay a solid foundation for evaluating the risk of LGG recurrence and malignant progression.

Construction of a novel molecular typing and scoring system for anoikis distinguishes between different prognostic risks and treatment responsiveness in low-grade glioma

“…The AUC value for OS prediction in the TCGA cohort was approximately 0.9, which was better than the existing common predictors. In contrast, a feature consisting of five LGG relapse and progression-associated genes had an AUC value of around 0.8 for OS prediction in the TCGA cohort ( 40 ), and another feature consisting of six TMB-associated genes also had an AUC value of around 0.8 for OS prediction in the TCGA cohort ( 41 ), which was lower than the AUC value in our study. The high predictive power of the risk score model is evident from the ROC, and the results of the calibration curve also suggest that the risk score model’s predictions corroborate quite well with the actual.…”

Molecular subtypes based on centrosome-related genes can predict prognosis and therapeutic responsiveness in patients with low-grade gliomas

“…Although it is commonly recognized that LGG has a better prognosis than GBM, LGG still recurs or advances after treatment ( 35 ). The centrosome is the main microtubule organization center in animal cells.…”

Predictors of tumor progression of low-grade glioma in adult patients within 5 years follow-up after surgery

“…Due to the invasive growth characteristics and the particularity of anatomical location of gliomas, single surgery or radiotherapy cannot avoid tumor recurrence ( 21 , 22 ). Low-grade gliomas account for 5% of intracranial tumors and can be classified into oligodendrogliomas, astrocytomas, and oligoastrocytomas, and mainly occur in younger patients, especially those in their 20 and 40 s. Imaging examination plays an important role in the diagnosis of glioma ( 23 , 24 ).…”