Department of Neurosurgery, Neurosurgery Centre, The First Affiliated Hospital of Xinjiang Medical University, No. 137, South Liyushan Road, Xinshi District, 830054, Urumqi, Xinjiang, China.
Department of Medical Laboratory, Xinjiang Production and Construction Corps Hospital, 830002, Urumqi, Xinjiang, China.
J Mol Neurosci. 2023 May;73(4-5):269-286. doi: 10.1007/s12031-023-02116-z. Epub 2023 Apr 17.
Lower WHO grade II and III gliomas (LGGs) exhibit significant genetic and transcriptional heterogeneity, and the heterogeneity of DNA damage repair (DDR) and its relationship to tumor biology, transcriptome, and tumor microenvironment (TME) remains poorly understood. In this study, we conducted multi-omics data integration to investigate DDR alterations in LGG. Based on clinical parameters and molecular characteristics, LGG patients were categorized into distinct DDR subtypes, namely, DDR-activated and DDR-suppressed subtypes. We compared gene mutation, immune spectrum, and immune cell infiltration between the two subtypes. DDR scores were generated to classify LGG patients based on DDR subtype features, and the results were validated using a multi-layer data cohort. We found that DDR activation was associated with poorer overall survival and that clinicopathological features of advanced age and higher grade were more common in the DDR-activated subtype. DDR-suppressed subtypes exhibited more frequent mutations in IDH1. In addition, we observed significant upregulation of activated immune cells in the DDR-activated subgroup, which suggests that immune cell infiltration significantly influences tumor progression and immunotherapeutic responses. Furthermore, we constructed a DDR signature for LGG using six DDR genes, which allowed for the division of patients into low- and high-risk groups. Quantitative real-time PCR results showed that CDK1, CDK2, TYMS, SMC4, and WEE1 were significantly upregulated in LGG samples compared to normal brain tissue samples. Overall, our study sheds light on DDR heterogeneity in LGG and provides insight into the molecular pathways of DDR involved in LGG development.
低级别世界卫生组织（WHO）分级 II 和 III 级神经胶质瘤（LGG）表现出显著的遗传和转录异质性，而 DNA 损伤修复（DDR）的异质性及其与肿瘤生物学、转录组和肿瘤微环境（TME）的关系仍知之甚少。在这项研究中，我们进行了多组学数据整合，以研究 LGG 中的 DDR 改变。根据临床参数和分子特征，将 LGG 患者分为不同的 DDR 亚型，即 DDR 激活型和 DDR 抑制型亚型。我们比较了两种亚型之间的基因突变、免疫谱和免疫细胞浸润。根据 DDR 亚型特征生成 DDR 评分，以对 LGG 患者进行分类，并使用多层数据队列进行验证。我们发现 DDR 激活与总生存期较差相关，并且在 DDR 激活亚型中更常见的是年龄较大和级别较高的临床病理特征。DDR 抑制型亚型中 IDH1 的突变更为频繁。此外，我们观察到 DDR 激活亚组中激活的免疫细胞显著上调，这表明免疫细胞浸润对肿瘤进展和免疫治疗反应有显著影响。此外，我们使用六个 DDR 基因构建了 LGG 的 DDR 特征，这使得患者可以分为低风险和高风险组。定量实时 PCR 结果显示，与正常脑组织样本相比，LGG 样本中 CDK1、CDK2、TYMS、SMC4 和 WEE1 的表达显著上调。总的来说，我们的研究揭示了 LGG 中 DDR 的异质性，并深入了解了参与 LGG 发展的 DDR 分子途径。
