[摘 要] 目的：通过生物信息学分析膜相关酪氨酸/苏氨酸蛋白激酶1（PKMYT1）在胶质瘤中的表达与预后价值、生物学功 能、药物敏感性、基因突变及免疫浸润的关联性。方法：基于中国胶质瘤基因组图谱数据库（CGGA）和癌症基因组图谱数据库 （TCGA）分析PKMYT1的差异表达情况。通过基因本体论分析（GO）和基因集富集分析（GSEA）预测PKMYT1可能富集的通路。 将PKMYT1与细胞周期相关基因和基因集进行Pearson相关性和基因集变异分析（GSVA）。进一步对PKMYT1高低表达组在胶 质瘤患者进行生存预后、基因突变、药物敏感性及免疫浸润分析。结果：PKMYT1在WHO高级别胶质瘤（P < 0.000 1）、异柠檬 酸脱氢酶（IDH）野生型胶质瘤（P < 0.05）和胶质母细胞瘤（P < 0.000 1）中显著高表达。PKMYT1低表达组患者的OS率显著高于 高表达组（P < 0.05）。Cox回归分析结果显示PKMYT1表达水平是OS的独立预后因素（P < 0.05）。GO和GSEA分析结果表明， 与PKMYT1共表达的基因集主要富集在细胞周期、DNA复制和DNA损伤修复等信号通路上。Pearson相关性和GSVA分析结果 显示，PKMYT1的表达与细胞周期相关基因、基因集及细胞周期检查点基因呈显著正相关（P < 0.01）。药物敏感性分析发现， PKMYT1高表达组患者对奥希替尼、达拉非尼、卡莫司汀和西地尼布具有较高敏感性（P < 0.05）。突变分析发现IDH1基因在 PKMYT1低表达组中具有更高的突变频率。免疫浸润分析结果表明，PKMYT1的表达与胶质瘤基质评分（r = 0.13，P < 0.001）、 免疫评分（r = 0.11，P < 0.01）和ESTIMATE评分（r = 0.13，P < 0.001）显著正相关；且与调节性T细胞（Treg细胞）和M2型巨噬细胞 的免疫细胞浸润水平显著正相关（P < 0.05）。结论：PKMYT1高表达的患者预后较差，其机制可能与肿瘤免疫浸润和细胞周期 调控有关。PKMYT1有望成为胶质瘤诊断和治疗的潜在靶点。

[Abstract] Objective: To analyze by bioinformatics the association between the expression of membrane-associated tyrosine/threonine protein kinase 1 (PKMYT1) in glioma with its prognostic value, biological function, drug sensitivity, gene mutation, and immune infiltration. Methods: The differential expression of PKMYT1 was analyzed based on the Chinese Glioma Genome Atlas database (CGGA) and the Cancer Genome Atlas database (TCGA). Pathways likely to be enriched for PKMYT1 were predicted by gene ontology analysis (GO) and gene set enrichment analysis (GSEA). PKMYT1 was subjected to Pearson correlation and gene set variation analysis (GSVA) with cell cycle-related genes and gene sets. The survival prognosis, gene mutation, drug sensitivity and immune infiltration were further analyzed for PKMYT1 high and low expression groups of glioma patients. Results: PKMYT1 was significantly highly expressed in WHO high-grade glioma (P < 0.000 1), IDH wild-type glioma (P < 0.05), and glioblastoma (P < 0.000 1). Overall survival (OS) of patients in the PKMYT1 low expression group was significantly higher than that of the high expression group (P < 0.05). Cox regression analysis showed that PKMYT1 expression level was an independent prognostic factor for OS (P < 0.05). GO and GSEA analyses showed that the gene sets co-expressed with PKMYT1 were mainly enriched in signaling pathways such as cell cycle, DNA replication and DNA damage repair. Pearson correlation and GSVA analyses showed that the expression of PKMYT1 was significantly and positively correlated with the cell cycle-related genes, gene sets and cell cycle checkpoint genes (P < 0.01). Drug sensitivity analysis revealed that patients in the PKMYT1 high expression group had high sensitivity osimertinib, dabrafenib, carmustine and cediranib (P < 0.05). Mutation analysis revealed that the IDH1 gene had a higher mutation frequency in the PKMYT1 low expression group. The results of immune infiltration analysis showed that PKMYT1 expression was significantly positively correlated with glioma stroma score (r = 0.13, P < 0.001), immune score (r = 0.11, P < 0.01) and ESTIMATE score (r = 0.13, P < 0.001); and was significantly positively correlated with immune cell infiltration level of regulatory T (Treg) cells and M2-type macrophages (P < 0.05). Conclusion: Patients with high PKMYT1 expression have a poorer prognosis, and the mechanism may be related to tumor immune infiltration and cell cycle regulation. PKMYT1 is expected to be a potential target for the diagnosis and treatment of glioma.

河北省自然科学基金-中医药联合基金培育项目（No. H2022209048）