目的通过生物信息学筛选与卵巢癌患者预后的坏死性凋亡相关基因。方法从公共数据库下载坏死性凋亡相关基因、卵巢癌的基因表达和相关临床数据,利用RStudio 4.1软件筛选出在卵巢癌组织与卵巢正常组织间差异表达的坏死性凋亡相关基因(差异表达基因),对差异表达基因进行基因本体论(GO)功能富集分析与京都基因与基因组百科全书(KEGG)通路富集分析。采用多因素COX回归模型筛选出与卵巢癌患者预后有关的坏死性凋亡相关基因。根据多因素COX回归结果构建卵巢癌预后风险模型,根据该模型风险评分中位数将卵巢癌样本分为高风险组和低风险组,采用Kaplan-Meier法比较高风险组和低风险组患者的生存情况,采用受试者工作特征(ROC)曲线验证卵巢癌预后风险模型的评估效能。通过COX回归模型分析卵巢癌预后的独立影响因素,并通过列线图展示卵巢癌独立预后影响因素与卵巢癌患者总生存率的相关性。结果(1)确定卵巢癌中有25个差异表达基因,包括13个上调基因与12个下调基因。(2)GO分析结果显示,差异表达基因涉及的生物学过程包括调节凋亡信号通路等,涉及的细胞组分主要为晚期内体膜等,涉及的分子功能主要包括细胞因子活性等。KEGG通路富集分析结果提示,差异表达基因主要富集在坏死性凋亡等信号通路。(3)多因素COX回归模型分析结果显示,信号转导与转录激活因子4(STAT4)基因和钙/钙调素依赖蛋白激酶Ⅱ型亚基α(CAMK2A)基因与卵巢癌患者预后相关(P<0.05),其中STAT4基因属于保护基因,CAMK2A基因为危险基因。(4)构建基于STAT4基因和CAMK2A基因的卵巢癌预后风险模型,生存分析结果显示高风险组患者总生存期低于低风险组(P<0.05),根据此模型评估卵巢癌患者1年、2年和3年生存情况的曲线下面积分别为0.575、0.616和0.593。(5)COX回归分析结果显示,该模型风险评分是卵巢癌患者预后的独立影响因素(P<0.05);基于卵巢癌独立预后影响因素构建的预测患者总生存期的列线图C指数折线图、列线图校准曲线分析结果提示列线图具有较好的准确性。结论坏死性凋亡相关基因中的STAT4基因和CAMK2A基因与卵巢癌患者预后相关,其中STAT4基因属于保护基因,CAMK2A基因为危险基因,基于STAT4基因和CAMK2A基因构建的卵巢癌预后风险模型对评估卵巢癌患者预后具有一定价值。
ObjectiveTo screen the necrotic apoptosis-related genes for prognosis of patients with ovarian cancer by bioinformatics. MethodsNecrotic apoptosis-related genes, expressions of ovarian cancerous genes, and relevant clinical data of ovarian cancer were downloaded from the public databases. Differentially expressed necrotic apoptosis-related genes (differentially expressed genes) between ovarian cancerous tissues and normal ovarian tissues were screened by employing the RStudio 4.1 software, and the Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on differentially expressed genes. The multivariate COX regression model was used to screen necrotic apoptosis-related genes related to prognosis of patients with ovarian cancer. According to the results of multivariate COX regression, the prognostic risk model of ovarian cancer was established, and ovarian cancerous samples were assigned to high-risk group or low-risk group according to median risk score of this model. The survival status was compared between the high-risk group and the low-risk group by using the Kaplan-Meier method. The receiver operating characteristic (ROC) curve was employed to validate evaluation efficiency of prognostic risk model of ovarian cancer. The independent influencing factors for prognosis of ovarian cancer were analyzed by the COX regression model, and the correlation of independent prognostic influencing factors for ovarian cancer with total survival rate of patients with ovarian cancer was presented by the nomogram. Results(1) A total of 25 differentially expressed genes were determined in ovarian cancer, including 13 up-regulated genes and 12 down-regulated genes. (2) The results of GO analysis revealed that differentially expressed genes involved biological processes including regulating apoptosis signaling pathway, etc.,involved cellular compositions mainly including endometrium in late stage, etc.,and involved molecular functions mainly containing cytokines activities, etc. The results of KEGG pathway enrichment analysis indicated that differentially expressed genes were mainly enriched in signaling pathways of necrotic apoptosis signaling pathway, etc. (3) The results of multivariate COX regression model analysis revealed that signal transducer and activator of transcription 4 (STAT4) gene and calcium/calmodulin dependent protein kinase Ⅱ alpha (CAMK2A) gene correlated with prognosis of patients with ovarian cancer (P<0.05), therein, STAT4 gene belonged to protective gene, and CAMK2A gene to risk gene. (4) The prognostic risk model of ovarian cancer was established based on STAT4 and CAMK2A genes. The results of survival analysis interpreted that the total survival of patients in the high-risk group was lower than that in the low-risk group (P<0.05); moreover, areas under the curve of 1-, 2-, and 3-year survival state in patients with ovarian cancer evaluated by this model were 0.575, 0.616, and 0.593, respectively. (5) The results of COX regression analysis interpreted that the risk score of this model was the independent influencing factor for prognosis of patients with ovarian cancer (P<0.05); in addition, the results of nomogram C-index line chart and nomogram calibration curve for predicting patients′ total survival established based on independent prognostic influencing factors of ovarian cancer indicated that the nomogram exerted relatively favorable accuracy.ConclusionSTAT4 and CAMK2A genes in necrotic apoptosis-related genes correlate with prognosis of patients with ovarian cancer, therein, STAT4 gene belongs to protective gene, and CAMK2A gene to risk gene. The prognostic risk model of ovarian cancer established based on STAT4 and CAMK2A genes exerts values on evaluating prognosis of patients with ovarian cancer to a certain extent.