摘要： 目的 研究复发胶质母细胞瘤与无复发胶质母细胞瘤组织的甲基化差异基因，并探讨其与患者无复发生存期（RFS）的关系。方法 从癌症基因组图谱（TCGA）数据库中下载胶质母细胞瘤患者的相关数据，筛选差异甲基化基因。采用Kaplan-Meier生存曲线分析基因表达水平与患者RFS的关系，采用单因素、多因素Cox回归分析鉴定胶质母细胞瘤独立预后标志物，采用MTT法检测细胞增殖水平。结果 通过比较复发组和无复发组，筛选出23个差异甲基化的CpG位点，这些CpG位点对应20个基因。进一步分析发现，复发组和无复发组中仅LysM结构域1 （LYSMD1）基因的表达水平存在统计学差异（P=0.024 9）。Kaplan-Meier生存曲线结果显示，LYSMD1高表达患者的RFS较LYSMD1低表达患者明显延长（P=0.031 3）。单因素、多因素Cox回归分析结果提示，LYSMD1 （多因素分析，HR=0.583，95% CI：0.384~0.886，P=0.012）为胶质母细胞瘤患者RFS的独立预后因素，LYSMD1低表达提示胶质母细胞瘤患者具有高复发风险。转染LYSMD1 cDNA至胶质瘤细胞后，与阴性质粒转染组相比，细胞增殖活性减弱（P<0.05）。结论 复发胶质母细胞瘤中LYSMD1基因甲基化水平升高，表达水平下调。LYSMD1可作为胶质母细胞瘤患者RFS的独立预后因素和潜在的治疗新靶点。

LysM结构域1基因甲基化在胶质母细胞瘤中的临床意义

吕洪涛¹, 李俊¹, 孙锡同²

1. 大连医科大学附属第一医院神经外科;
2. 大连医科大学附属第一医院急诊科, 辽宁 大连 116011

收稿日期:2020-11-02出版日期:2021-06-30发布日期:2021-05-28
通讯作者:孙锡同E-mail:sunxitong23@126.com
作者简介:吕洪涛(1981-),男,副主任医师,博士.
基金资助:辽宁省自然科学基金（2019-ZD-0646）


关键词: 胶质母细胞瘤, 无复发生存期, 甲基化, 预后标志物
Abstract: Objective To investigate the differential methylation of genes between recurrent and non-recurrent glioblastoma tissue specimens,and explore the relationship between these genes and recurrence-free survival (RFS) of patients. Methods Relevant data of glioblastoma patients were downloaded from the Cancer Genome Atlas (TCGA) database to screen out the differential methylated genes. Kaplan-Meier analysis was used to analyze the association between the expression of these genes and RFS. Univariate and multivariate Cox regression analyses were utilized to identify the prognostic biomarkers. Cell proliferation was tested by in vitro MTT assay. Results On comparing the recurrent and non-recurrent groups,23 differentially methylated CpG sites were identified,corresponding to 20 genes. Further analysis revealed that there was a significant difference in the LYSMD1 gene expression levels between the recurrent and non-recurrent groups (P=0.024 9). Kaplan-Meier analysis indicated that the patients with a high LYSMD1 expression had a significantly longer RFS than those with a low LYSMD1 expression (P=0.031 3). Univariate and multivariate Cox regression analyses demonstrated that LYSMD1 (multivariate,hazard ratio=0.583,95% confidence interval:0.384-0.886,P=0.012) was an independent prognostic factor for RFS in glioblastoma patients,and patients with a low expression of LYSMD1 tended to have a higher risk of recurrence. Moreover,LYSMD1 overexpression decreased the proliferation of glioma cells when compared with a transfected negative control (P<0.05). Conclusion LYSMD1 gene is hypermethylated and its expression is down-regulated in recurrent glioblastoma patients. LYSMD1 may be an independent prognostic factor for RFS as well as a potential therapeutic candidate in glioblastoma patients.
Key words: glioblastoma, recurrence-free survival, methylation, prognostic biomarker
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