Identification of Prognostic Genes in Gliomas Based on Increased Microenvironment Stiffness

Abstract

With a median survival time of 15 months, glioblastoma multiforme is one of the most aggressive primary brain cancers. The crucial roles played by the extracellular matrix (ECM) stiffness in glioma progression and treatment resistance have been reported in numerous studies. However, the association between ECM-stiffness-regulated genes and the prognosis of glioma patients remains to be explored. Thus, using bioinformatics analysis, we first identified 180 stiffness-dependent genes from an RNA-Seq dataset, and then evaluated their prognosis in The Cancer Genome Atlas (TCGA) glioma dataset. Our results showed that 11 stiffness-dependent genes common between low- and high-grade gliomas were prognostic. After validation using the Chinese Glioma Genome Atlas (CGGA) database, we further identified four stiffness-dependent prognostic genes: FN1, ITGA5, OSMR, and NGFR. In addition to high-grade glioma, overexpression of the four-gene signature also showed poor prognosis in low-grade glioma patients. Moreover, our analysis confirmed that the expression levels of stiffness-dependent prognostic genes in high-grade glioma were significantly higher than in low-grade glioma, suggesting that these genes were associated with glioma progression. Based on a pathophysiology-inspired approach, our findings illuminate the link between ECM stiffness and the prognosis of glioma patients and suggest a signature of four stiffness-dependent genes as potential therapeutic targets.

REFINED-CNN framework for survival prediction with high-dimensional features

“…The top identified genes for the GBM/LGG cancer align with recent findings. For instance, the SDR39U1 was found as one of the prognostic factors in LGG using a multivariate Cox regression model; 21 ADD3 is predictor of shorter survival and has significant association with tumor grade; 22 DHX33 is discovered to be highly expressed in glioblastoma multiforme; 23 the EMP2 , one of the PMP22 gene families, is up-regulated in GBM/LGG; 24 SLC25A16 is a mitochondrial carrier protein that is highly suppressed in GBM/LGG; 25 ZNF286A is one of the zinc-finger proteins (an oncogene in GBM/LGG); 26 ENO2 is a highly expressed gene in GBM/LGG with high prognosis factor; 27 PAR s are a family of genes that are highly correlated with short survival in GBM/LGG. 28

Figure 4 Risk scores of genes in GBM/LGG cancer identified from the model The global risk score of the most influential genes computed with 5-fold cross-validation.

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Prognostic relevance and validation of ARPC1A in the progression of low-grade glioma

“…Exogenous FNDC4 effectively impaired the M1 polarization of M0 macrophages independently without affecting M2 polarization [49]. Furthermore, the overexpression of gene signatures such as FN1, ITGA5, OSMR, and NGFR from the TCGA database is associated with poor prognosis in LGG patients [50]. A total of 1489 gene signatures have been identified which have a significant correlation with the prognosis of LGG patients.…”

Влияние Новых Диагностических Критериев ВОЗ На Значимость Биомаркеров Глиом, Включая Уровни Активации Молекулярных Путей И Экспрессию Генов

“…По-видимому, это обусловлено тем, что до 2021 года «глиобластомы, IV степени» включали в себя как опухоли с IDH1/2 дикого типа, так и IDH-мутантные. Вероятно, с этим же связано то, что протестированные прогностические маркеры (например, генные подписи [3,4] и уровень активации пути FREM2 [2]) утратили свою прогностическую значимость при переходе от старой к актуальной классификации глиом. Стоит отметить, что использование уровней активации молекулярных путей (PAL) давало лучшие результаты по сравнению с уровнями экспрессии отдельных генов как для «старой», так и для «новой» классификации глиом.…”