Department of Biostatistics and Epidemiology, School of Public Health, Shenzhen University Medical School, Shenzhen, Guangdong, People's Republic of China.
Department of General Practice, The Affiliated Luohu Hospital of Shenzhen University Medical School, Shenzhen, Guangdong, People's Republic of China.
Mol Carcinog. 2023 Dec;62(12):1832-1845. doi: 10.1002/mc.23618. Epub 2023 Aug 10.
Aberrant DNA methylation is a critical regulator of gene expression in the development and progression of glioblastoma (GBM). However, the impact of methylation-driven gene PCDHB4 changes on GBM occurrence and progression remains unclear. Therefore, this study aimed to identify the PCDHB4 gene for early diagnosis and prognostic evaluation and clarify its functional role in GBM. Methylation-driven gene PCDHB4 was selected for GBM using the multi-omics integration method based on publicly available data sets. The diagnostic capabilities of PCDHB4 methylation and 5-hydroxymethylcytosines were validated in tissue and blood cell-free DNA (cfDNA) samples, respectively. Combined survival analysis of PCDHB4 methylation and immune infiltration cells evaluated the prognostic predictive performance of GBM patients. We identified that the PCDHB4 gene achieved high discriminative capabilities for GBM and normal tissues with an area under the curve value of 0.941. PCDHB4 hypermethylation was observed in cfDNA blood samples from GBM patients. Compared with GBM patients with PCDHB4 hypermethylation level, patients with PCDHB4 hypomethylation level had significantly poorer overall survival (p = 0.035). In addition, GBM patients with PCDHB4 hypermethylation and high infiltration of CD4 T cell activation level had a favorable survival (p = 0.026). Moreover, we demonstrated that mRNA expression of PCDHB4 was downregulated in GBM tissues and upregulated in GBM cell lines with PCDHB4 demethylation, and PCDHB4 overexpression inhibited GBM cell proliferation and migration. In summary, we discovered a novel methylation-driven gene PCDHB4 for the diagnosis and prognosis of GBM and demonstrated that PCDHB4 is a tumor suppressor in vitro experiments.
DNA 甲基化异常是胶质母细胞瘤（GBM）发生和发展中基因表达的关键调控因子。然而，甲基化驱动的基因 PCDHB4 变化对 GBM 发生和进展的影响尚不清楚。因此，本研究旨在鉴定 PCDHB4 基因，用于早期诊断和预后评估，并阐明其在 GBM 中的功能作用。
使用基于公开数据集的多组学整合方法，选择甲基化驱动的基因 PCDHB4 用于 GBM。分别在组织和无细胞游离 DNA（cfDNA）样本中验证 PCDHB4 甲基化和 5-羟甲基胞嘧啶的诊断能力。PCDHB4 甲基化与免疫浸润细胞的联合生存分析评估了 GBM 患者的预后预测性能。
我们发现 PCDHB4 基因对 GBM 和正常组织具有高区分能力，曲线下面积值为 0.941。在 GBM 患者的 cfDNA 血样中观察到 PCDHB4 高甲基化。与 PCDHB4 高甲基化水平的 GBM 患者相比，PCDHB4 低甲基化水平的患者总生存期明显较差（p=0.035）。此外，PCDHB4 高甲基化和 CD4 T 细胞激活水平高浸润的 GBM 患者生存良好（p=0.026）。
此外，我们证明了 PCDHB4 在 GBM 组织中的 mRNA 表达下调，在 PCDHB4 去甲基化的 GBM 细胞系中上调，PCDHB4 过表达抑制了 GBM 细胞的增殖和迁移。
总之，我们发现了一个新的甲基化驱动基因 PCDHB4 用于 GBM 的诊断和预后，并在体外实验中证明了 PCDHB4 是一种肿瘤抑制基因。
