目的 导致低级别胶质瘤（low grade glioma,LGG）预后和治疗效果差的主要因素包括复发和恶性进展。防止癌细胞从S期过早进入G2期对肿瘤的侵袭和转移至关重要,其分子机制在LGG中仍存在研究空白。探讨基于S/G2风险跨越（risk crossing at S/G2 phase,RASG2）相关基因的分子亚型对LGG患者预后及治疗反应性的预测价值。方法 我们从癌症基因组图谱（the cancer genome atlas,TCGA）的LGG队列中下载了509个样本的数据。根据7个RASG2相关基因进行聚类分析鉴定不同亚型,并评估不同亚型在临床病理学和生物学特征上的差异。ESTIMATE算法和单样本基因集富集分析用于解析LGG的肿瘤免疫微环境（tumor immune microenvironment,TIME）。利用Cox回归分析、最小绝对收缩与选择操作器回归和随机森林算法创建了一个预测评分系统。该评分系统用于将LGG患者划分为高RASG2S（risk crossing at S/G2 phase score）组和低RASG2S组。通过基于TCGA与中国胶质瘤基因组图谱（Chinese glioma genome atlas,CGGA）队列的突变分析、生存分析和药物敏感性分析,评估了RASG2S与LGG患者的基因突变情况、预后、治疗响应性的关联。通过细胞实验验证了以TICRR和MTBP为核心的RASG2基因组在LGG细胞和正常细胞之间的差异表达,以及对LGG增殖、侵袭能力的影响。结果 根据7个RASG2相关基因的表达谱,所有LGG患者被分为A和B两种亚型。两种亚型患者具有截然不同的预后与TIME浸润特征。进一步构建的RASG2S可独立预测LGG的预后与治疗响应性,低RASG2S组患者的预后显著更好,具有更高的异柠檬酸脱氢酶（isocitrate dehydrogenase,IDH）突变、1p19q共缺失比例,但具有更低的TIME免疫细胞浸润、肿瘤突变负荷及更高的替莫唑胺敏感性。结论 本研究揭示了一种新的RASG2相关基因特征,可用于预测LGG患者的预后和治疗响应性,这可能有助于LGG精准治疗的临床决策。
Abstract
Objective The major factors contributing to poor prognosis and treatment outcome in low grade glioma (LGG) include recurrence and malignant progression. Preventing cancer cells from prematurely entering the G2 stage from the S stage is crucial for tumor invasion and metastasis, and its molecular mechanisms still have research gaps in LGG. To investigate the predictive value of molecular isoforms based on risk crossing at S/G2 phase (RASG2) related genes on the prognosis and treatment responsiveness of LGG patients. Methods We downloaded data from 509 samples from the TCGA-LGG cohort, performed cluster analysis to identify different subtypes based on seven RASG2-related genes, and assessed subtype differences in clinicopathological and biological features. Estimation and single-sample gene set enrichment analyses were used to parse the tumor immune microenvironment (TIME) for LGG. A predictive scoring system was created using Cox regression analysis, Least Absolute Shrinkage with Selection Operator regression, and the Random Forest algorithm. This scoring system was used to categorize LGG patients into a high RASG2S (risk crossing at S/G2 phase score) group and a low RASG2S group. The association of RASG2S with the mutation status, prognosis, and treatment responsiveness of LGG patients was evaluated by mutation analysis, survival analysis, and drug sensitivity analysis based on the TCGA and CGGA cohorts. The differential expression of the RASG2 gene, centered on TICRR and MTBP, between LGG cells and normal cells, and its effect on the proliferation and invasive ability of LGG were verified by cellular experiments. Results All LGG patients were categorized into two subtypes, A and B, based on the expression profiles of seven RASG2-related genes. Patients with the two subtypes had distinct prognosis and TIME infiltration characteristics. Further constructed RASG2S independently predicted the prognosis and treatment responsiveness of LGG, and patients in the low RASG2S group had a significantly better prognosis, with a higher proportion of IDH mutations, 1p19q co-deletions, but with lower TIME immune cell infiltration, tumor mutational load and higher temozolomide sensitivity. Conclusion This study reveals a novel RASG2-associated gene signature that can be used to predict prognosis and treatment responsiveness in patients with LGG, which may contribute to clinical decision-making for precision treatment of LGG.
关键词
低级别胶质瘤 /
S/G2风险跨越 /
预后 /
免疫疗法 /
替莫唑胺
Key words
low-grade glioma /
risk crossing at S/G2 phase /
prognosis /
immunotherapy, temozolomide
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基金
国家自然科学基金青年科学基金项目“VEGFA rs2010963多态性与放射性口腔黏膜炎的关联机制及应用研究”（81502658）; 湖南省卫生高层次人才科研项目“2023年卫生健康高层次人才”（20240304101）
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