鉴定 DNA 甲基化调控的 WEE1，其对低级别胶质瘤的预后和免疫治疗具有潜在意义。

Identification of DNA methylation-regulated WEE1 with potential implications in prognosis and immunotherapy for low-grade glioma.

机构信息

Laboratory Center, Huizhou Third People's Hospital, Affiliated Hospital of Guangzhou Medical University, Huizhou, China.

Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

出版信息

Cancer Biomark. 2024;40(3-4):297-317. doi: 10.3233/CBM-230517.

DOI:10.3233/CBM-230517

PMID:39213054

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11380252/

Abstract

BACKGROUND

WEE1 is a critical kinase in the DNA damage response pathway and has been shown to be effective in treating serous uterine cancer. However, its role in gliomas, specifically low-grade glioma (LGG), remains unclear. The impact of DNA methylation on WEE1 expression and its correlation with the immune landscape in gliomas also need further investigation.

METHODS

This study used data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) and utilized various bioinformatics tools to analyze gene expression, survival, gene correlation, immune score, immune infiltration, genomic alterations, tumor mutation burden, microsatellite instability, clinical characteristics of glioma patients, WEE1 DNA methylation, prognostic analysis, single-cell gene expression distribution in glioma tissue samples, and immunotherapy response prediction based on WEE1 expression.

RESULTS

WEE1 was upregulated in LGG and glioblastoma (GBM), but it had a more significant prognostic impact in LGG compared to other cancers. High WEE1 expression was associated with poorer prognosis in LGG, particularly when combined with wild-type IDH. The WEE1 inhibitor MK-1775 effectively inhibited the proliferation and migration of LGG cell lines, which were more sensitive to WEE1 inhibition. DNA methylation negatively regulated WEE1, and high DNA hypermethylation of WEE1 was associated with better prognosis in LGG than in GBM. Combining WEE1 inhibition and DNA methyltransferase inhibition showed a synergistic effect. Additionally, downregulation of WEE1 had favorable predictive value in immunotherapy response. Co-expression network analysis identified key genes involved in WEE1-mediated regulation of immune landscape, differentiation, and metastasis in LGG.

CONCLUSION

Our study shows that WEE1 is a promising indicator for targeted therapy and prognosis evaluation. Notably, significant differences were observed in the role of WEE1 between LGG and GBM. Further investigation into WEE1 inhibition, either in combination with DNA methyltransferase inhibition or immunotherapy, is warranted in the context of LGG.

摘要

背景

WEE1 是 DNA 损伤反应途径中的关键激酶，已被证明在治疗浆液性子宫癌方面有效。然而，它在神经胶质瘤中的作用，特别是低级别神经胶质瘤（LGG），仍不清楚。WEE1 表达的 DNA 甲基化及其与神经胶质瘤免疫图谱的相关性也需要进一步研究。

方法

本研究使用了来自癌症基因组图谱（TCGA）、中国脑胶质瘤基因组图谱（CGGA）和基因表达综合数据库（GEO）的数据，并利用各种生物信息学工具分析基因表达、生存、基因相关性、免疫评分、免疫浸润、基因组改变、肿瘤突变负荷、微卫星不稳定性、胶质瘤患者的临床特征、WEE1 DNA 甲基化、预后分析、胶质瘤组织样本中的单细胞基因表达分布以及基于 WEE1 表达的免疫治疗反应预测。

结果

WEE1 在 LGG 和胶质母细胞瘤（GBM）中上调，但与其他癌症相比，它在 LGG 中具有更显著的预后影响。WEE1 高表达与 LGG 的不良预后相关，特别是与野生型 IDH 结合时。WEE1 抑制剂 MK-1775 能有效抑制 LGG 细胞系的增殖和迁移，这些细胞系对 WEE1 抑制更为敏感。DNA 甲基化负调控 WEE1，LGG 中 WEE1 的高 DNA 高甲基化与比 GBM 更好的预后相关。WEE1 抑制与 DNA 甲基转移酶抑制联合具有协同作用。此外，WEE1 的下调在免疫治疗反应预测中具有良好的预测价值。共表达网络分析确定了 WEE1 介导的 LGG 中免疫景观、分化和转移调节的关键基因。