Zenghui Qian1,2, Yiming Li1,2, Xing Fan1,2, Chuanbao Zhang1,2, Yinyan Wang1,2, Tao Jiang1,2,3, Xing Liu1,2,4. 1. Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. 2. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. 3. Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, China. 4. Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
Abstract
Background: Mutations in isocitrate dehydrogenase (IDH) affect the development and prognosis of gliomas. We investigated the role of IDH mutations in the regulation of immune phenotype in lower-grade gliomas (LGGs).Method and patients: A total of 1,008 cases with clinical and IDH mutation data from five cohorts were enrolled. Samples with RNA sequencing data from the Chinese Glioma Genome Atlas (CGGA) were used as training set, whereas RNA data from the Cancer Genome Atlas, Repository for Molecular Brain Neoplasia, GSE16011, and CGGA microarray databases were used for validation. R language tools and bioinformatics analysis were used for gene signature construction and biological function annotation. Results: We found that IDH mutations caused down-regulation of local immune response as among 332 immune system-related genes, 196(59.0%) were differentially expressed according to IDH mutation status. Nearly 70% of those differentially expressed genes exhibited prognostic value in LGGs. An immune response-based gene signature was constructed that distinguished cases with high- or low-risk of unfavorable prognosis and remained an independent prognostic factor in multivariate analyses in both training and validation cohorts. Samples from high-risk cases exhibited elevated expression of genes involved in immune response and NF-κB pathway activation. Furthermore, we found a strong correlation between the risk score and T cells, macrophage-related immune response, and expression of several prominent immune checkpoints. Conclusion: Our results indicated that mutant IDH is highly associated with the regulation of the immune microenvironment in LGGs. The observed immune system gene signature, which was sensitive to IDH mutation status, efficiently predicted patient survival.
Background: Mutations in isocitrate dehydrogenase (IDH) affect the development and prognosis of gliomas. We investigated the role of IDH mutations in the regulation of immune phenotype in lower-grade gliomas (LGGs).Method and patients: A total of 1,008 cases with clinical and IDH mutation data from five cohorts were enrolled. Samples with RNA sequencing data from the Chinese Glioma Genome Atlas (CGGA) were used as training set, whereas RNA data from the Cancer Genome Atlas, Repository for Molecular Brain Neoplasia, GSE16011, and CGGA microarray databases were used for validation. R language tools and bioinformatics analysis were used for gene signature construction and biological function annotation. Results: We found that IDH mutations caused down-regulation of local immune response as among 332 immune system-related genes, 196(59.0%) were differentially expressed according to IDH mutation status. Nearly 70% of those differentially expressed genes exhibited prognostic value in LGGs. An immune response-based gene signature was constructed that distinguished cases with high- or low-risk of unfavorable prognosis and remained an independent prognostic factor in multivariate analyses in both training and validation cohorts. Samples from high-risk cases exhibited elevated expression of genes involved in immune response and NF-κB pathway activation. Furthermore, we found a strong correlation between the risk score and T cells, macrophage-related immune response, and expression of several prominent immune checkpoints. Conclusion: Our results indicated that mutant IDH is highly associated with the regulation of the immune microenvironment in LGGs. The observed immune system gene signature, which was sensitive to IDH mutation status, efficiently predicted patient survival.
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