摘要： 目的 探讨喹啉酸磷酸核糖转移酶（QPRT）在胶质瘤中的表达情况及其与临床病理学特征和患者预后的关系。方法 基于肿瘤基因组学图谱计划、TARGET、GTEx、GEPIA2和UALCAN等公共数据库，对QPRT基因在胶质瘤中表达量及其与患者疾病特异性生存期、总生存期、无进展生存期的关系进行分析。纳入2010年7月至2018年12月在新疆医科大学第一附属医院经病理确诊的219例胶质瘤患者，免疫组化染色检测低级别胶质瘤和胶质母细胞瘤QPRT阳性率，采用单因素Log-rank检验和多因素Cox比例风险回归筛查胶质瘤患者生存状态影响因素，单因素和多因素Logistic回归分析筛查总生存期和无进展生存期危险因素。结果 基于公共数据库的生物信息学分析显示，QPRT基因在胶质母细胞瘤与低级别胶质瘤综合队列（GBMLGG）、低级别胶质瘤和胶质母细胞瘤中均呈高表达（P=0.000，0.000，0.000），QPRT基因表达量与低级别胶质瘤和胶质母细胞瘤的免疫细胞浸润评分显著相关，与GBMLGG（P=0.000）、低级别胶质瘤（P=0.000）和胶质母细胞瘤（P=0.000）患者年龄呈正相关；GBMLGG、低级别胶质瘤和胶质母细胞瘤与肿瘤突变负荷呈负相关（P=0.000，0.000，0.000）、与微卫星不稳定性呈正相关（P=0.001，0.019，0.032）。免疫组化染色显示，QPRT阳性率为59.82%（131/219），QPRT阳性组患者年龄> 50岁（P=0.027）、术后辅以放化疗（P=0.021）、胶质母细胞瘤（P=0.000）、死亡（P=0.000）、进展（P=0.000）和肿瘤复发（P=0.000）比例均高于QPRT阴性组，总生存期（P=0.000）和无进展生存期（P=0.000）短于QPRT阴性组。Logistic回归分析显示，年龄> 50岁（OR=2.149，95% CI： 1.037~4.453；P=0.040）、胶质母细胞瘤（OR=10.269，95% CI：3.635~29.013；P=0.000）和QPRT阳性（OR=5.444，95% CI：2.675~11.080；P=0.000）是胶质瘤患者死亡的危险因素，胶质母细胞瘤（OR=28.821，95% CI：3.409~243.648；P=0.002）、肿瘤复发（OR=23.538，95% CI：2.836~195.336；P=0.003）和QPRT阳性（OR=6.323，95% CI：2.850~14.025；P=0.000）是进展生存的危险因素。Cox比例风险回归分析显示，胶质母细胞瘤（RR=8.330，95% CI：4.727~14.681；P=0.000）和QPRT阳性（RR=1.692，95% CI： 1.066~2.685；P=0.026）是胶质瘤患者总生存期缩短的危险因素，肿瘤未复发是总生存期延长的保护因素（RR=0.507，95% CI：0.314~0.819；P=0.006）；胶质母细胞瘤（RR=5.825，95% CI：3.436~9.876；P=0.000）和QPRT阳性（RR=1.548，95% CI：1.017~2.356；P=0.041）是胶质瘤患者无进展生存期缩短的危险因素。结论 QPRT基因在胶质瘤中呈高表达，是影响胶质瘤患者总生存期和无进展生存期的独立危险因素，提示QPRT可以作为预测胶质瘤预后的潜在分子标志物。

关键词: 神经胶质瘤, 喹啉酸类, 基因表达, 预后, 计算生物学, 免疫组织化学, Logistic模型, 比例危险度模型

Abstract: Objective To investigate the expression of quinolinic acid phosphoribosyltransferase (QPRT) in glioma patients and its associations with clinicopathological features and prognosis. Methods Public databases including The Cancer Genome Atlas (TCGA), TARGET, GTEx, GEPIA2 and UALCAN were used to analyze QPRT expression in glioma and its relationships with disease-specific survival (DSS), overall survival (OS) and progression free survival (PFS). Additionally, 219 pathologically confirmed glioma cases treated at The First Affiliated Hospital of Xinjiang Medical University from July 2010 to December 2018 were enrolled. Immunohistochemical staining was performed to determine QPRT positivity in lower-grade glioma (LGG) and glioblastoma (GBM). Factors affecting survival were identified using Log-rank test and multivariable Cox proportional hazards regression. Univariable and multivariable Logistic regression analyses were conducted to screen risk factors for OS and PFS in glioma patients. Results Bioinformatic analyses showed that QPRT was highly expressed in the combined GBM and LGG (GBMLGG) cohort, LGG and GBM (P=0.000, 0.000, 0.000). QPRT expression was significantly correlated with immune cell infiltration scores in both LGG and GBM. It was positively associated with age in the GBMLGG cohort, LGG and GBM (P=0.000, 0.000, 0.000). It was negatively associated with tumor mutational burden (TMB) in the GBMLGG cohort, LGG and GBM (P=0.000, 0.000, 0.000), and positively associated with microsatellite instability (MSI; P=0.001, 0.019, 0.032). Immunohistochemical staining based on clinical samples showed a QPRT positivity rate was 59.82% (131/219). Compared with the QPRT-negative group, the QPRT-positive group had higher proportions of age > 50 years (P=0.027), receipt of adjuvant chemoradiotherapy (P=0.021), GBM diagnosis (P=0.000), death (P=0.000), disease progression (P=0.000) and tumor recurrence (P=0.000), and had shorter OS (P=0.000) and PFS (P=0.000). Logistic regression showed age > 50 years (OR=2.149, 95%CI: 1.037-4.453; P=0.040), GBM (OR=10.269, 95%CI: 3.635-29.013; P=0.000), and QPRT positivity (OR=5.444, 95%CI: 2.675-11.080; P=0.000) were risk factors for death; GBM (OR=28.821, 95%CI: 3.409-243.648; P=0.002), tumor recurrence (OR=23.538, 95%CI: 2.836-195.336; P=0.003) and QPRT positivity (OR=6.323, 95%CI: 2.850-14.025; P=0.000) were risk factors for progression. Cox proportional hazards regression analysis showed that GBM (RR=8.330, 95%CI: 4.727-14.681; P=0.000) and QPRT positivity (RR=1.692, 95%CI: 1.066-2.685; P=0.026) were risk factors for worse OS, while absence of recurrence was protective (RR=0.507, 95%CI: 0.314-0.819; P=0.006). For PFS, GBM (RR=5.825, 95%CI: 3.436-9.876; P=0.000) and QPRT positivity (RR=1.548, 95%CI: 1.017-2.356; P=0.041) were risk factors. Conclusions QPRT is highly expressed in glioma and serves as an independent risk factor for poorer OS and PFS, suggesting that QPRT may be a potential molecular biomarker for prognostication in glioma.

Key words: Glioma, Quinolinic acids, Gene expression, Prognosis, Computational biology, Immunohistochemistry, Logistic models, Proportional hazards models