Abstract
Since autophagy and the immune microenvironment are deeply involved in the tumor development and progression of Lower-grade gliomas (LGG), our study aimed to construct an autophagy-related risk model for prognosis prediction and investigate the relationship between the immune microenvironment and risk signature in LGG. Therefore, we identified six autophagy-related genes (BAG1, PTK6, EEF2, PEA15, ITGA6, and MAP1LC3C) to build in the training cohort (n = 305 patients) and verify the prognostic model in the validation cohort (n = 128) and the whole cohort (n = 433), based on the data from The Cancer Genome Atlas (TCGA). The six-gene risk signature could divide LGG patients into high- and low-risk groups with distinct overall survival in multiple cohorts (all p < 0.001). The prognostic effect was assessed by area under the time-dependent ROC (t-ROC) analysis in the training, validation, and whole cohorts, in which the AUC value at the survival time of 5 years was 0.837, 0.755, and 0.803, respectively. Cox regression analysis demonstrated that the risk model was an independent risk predictor of OS (HR > 1, p < 0.05). A nomogram including the traditional clinical parameters and risk signature was constructed, and t-ROC, C-index, and calibration curves confirmed its robust predictive capacity. KM analysis revealed a significant difference in the subgroup analyses’ survival. Functional enrichment analysis revealed that these autophagy-related signatures were mainly involved in the phagosome and immune-related pathways. Besides, we also found significant differences in immune cell infiltration and immunotherapy targets between risk groups. In conclusion, we built a powerful predictive signature and explored immune components (including immune cells and emerging immunotherapy targets) in LGG.
Highlights
Diffuse low-grade and intermediate-grade gliomas including WHO grades II and III, hereafter called lower-grade gliomas (LGG) (Cancer Genome Atlas Research et al, 2015)
Go enrichment analysis revealed that the biological process of the DE-autophagy-related genes (ARGs) were significantly enriched in terms of autophagy-related processes; the cellular component of the differentially expressed autophagy-related genes (DE-ARGs) were significantly enriched in the terms autophagosome membrane, autophagosome and vacuolar membrane and the molecular function of the DE-ARGs were significantly enriched in the terms ubiquitin and ubiquitin−like protein ligase binding, and cyclin−dependent protein serine/ threonine kinase inhibitor activity (Figure 1C)
We found the gene expressions of multiple promising immunotherapy targets, including CD47, CD276, CTLA-4, LAG3, PD-1/L1, and TIM3, and tumor mutation burden (TMB) were significantly increased in the high-risk group, while the expression levels of NKG2A was significantly upregulated in the low-risk group than in the high-risk group (Figure 9B)
Summary
Diffuse low-grade and intermediate-grade gliomas including WHO grades II and III, hereafter called lower-grade gliomas (LGG) (Cancer Genome Atlas Research et al, 2015). Several genetic biomarkers were incorporated into the 2016 WHO classification, including chromosome arms 1p and 19q codeletion, isocitrate dehydrogenase (IDH) mutation, and O-6-methylguanine-DNA methyltransferase (MGMT) methylation, to illuminate the histological characteristics and guide the therapeutic approach (Hartmann et al, 2010; Wick et al, 2013; Hainfellner et al, 2014; Louis et al, 2016). These widely utilized biomarkers in LGG have recently been discovered, the novel predictors of clinical outcomes or therapeutic targets for LGG are not fully unraveled
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