肝细胞癌病人线粒体DNA拷贝数与临床病理特征的关系及对预后的影响

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目的:探讨肝细胞癌病人线粒体DNA拷贝数与临床病理特征的关系及对预后的影响。方法:采用回顾性队列研究方法。收集2011年3—6月海军军医大学附属东方肝胆外科医院收治的71例行手术切除肝细胞癌病人的临床病理资料;男61例,女10例;中位年龄为55岁,年龄范围为26~80岁。所有病人检测肝癌组织和癌旁组织线粒体DNA拷贝数。观察指标:(1)肝细胞癌病人肝癌组织和癌旁组织线粒体DNA拷贝数及其与临床病理特征的关系。(2)随访情况。(3)肝细胞癌病人预后影响因素分析。采用门诊或电话方式进行随访,了解病人术后生存情况。随访时间截至2019年9月。正态分布的计量资料以n x±s表示,组间比较采用独立样本n t检验或配对样本n t检验。偏态分布的计量资料以n M(范围)表示。计数资料以绝对数表示,组间比较采用n χ2检验或Fisher确切概率法。单因素和多因素分析均采用COX回归模型,单因素分析中n P<0.10的指标纳入多因素分析。采用Kaplan-Meier法计算生存率和绘制生存曲线,采用Log-rank检验进行生存分析。n 结果:(1)肝细胞癌病人肝癌组织和癌旁组织线粒体DNA拷贝数及其与临床病理特征的关系:71例肝细胞癌病人肝癌组织线粒体DNA拷贝数为0.85±0.08,癌旁组织线粒体DNA拷贝数为1.16±0.08,两者比较,差异有统计学意义(n t=2.96,n P<0.05)。71例病人中,48例为线粒体DNA低拷贝数,23例为线粒体DNA高拷贝数。线粒体DNA低拷贝数和高拷贝数病人肿瘤包膜(完整、不完整)和微血管侵犯(有、无)分别为20、28例,21、27例和16、7例,4、19例,上述指标比较,差异均有统计学意义(n χ2n =4.84,4.74,n P<0.05)。(2)随访情况:71例病人均获得随访,随访时间为2.1~85.3个月,中位随访时间为47.8个月。71例病人1、3、5年总体生存率分别为87.3%、64.7%、37.4%。48例线粒体DNA低拷贝数病人1、3、5年总体生存率分别为81.2%、50.0%、29.2%;23例线粒体DNA高拷贝数病人1、3、5年总体生存率分别为95.7%、86.5%、54.7%,两者生存情况比较,差异有统计学意义(n χ2n =5.86,n P<0.05)。(3)肝细胞癌病人预后影响因素分析:单因素分析结果显示肿瘤数目、门静脉癌栓、微血管侵犯、巴塞罗那临床肝癌分期、线粒体DNA拷贝数是影响肝细胞癌病人预后的相关因素(风险比=2.211,2.911,3.899,3.587,0.440,95%可信区间为1.024~4.777,1.485~5.704,2.115~7.186,1.615~7.966,0.223~0.871,n P<0.05)。多因素分析结果显示:微血管侵犯和线粒体DNA拷贝数是肝细胞癌病人预后的独立影响因素(风险比=2.754,0.437,95%可信区间为1.374~5.521,0.205~0.932,n P<0.05)。n 结论:肝细胞癌病人线粒体DNA拷贝数与肿瘤包膜、微血管侵犯有关;微血管侵犯和线粒体DNA拷贝数是肝细胞癌病人预后的独立影响因素。“,”Objective:To investigate the relationship of mitochondrial DNA (mtDNA) copy number with clinicopathologic characteristics and its influence on the prognosis of hepatocellular carcinoma (HCC) patients.Methods:The retrospective case-control study was conducted. The clinicopathological data of 71 HCC patients undergoing surgical treatment in the Eastern Hepatobiliary Surgery Hospital of Naval Medical University from March to June 2011 were collected. There were 61 males and 10 females, aged from 26 to 80 years, with a median age of 55 years. The mtDNA copy number of tumor tissues and adjacent normal tissues were measured for all patients. Observation indicators: (1) the mtDNA copy number of tumor tissues and adjacent normal tissues and relationship between the mtDNA copy number and clinicopathological characteristics of HCC patients; (2) follow-up; (3) related factors for the prognosis of HCC patients. Follow-up using outpatient examination or telephone interview was conducted to detect postoperative survival of patients up to September 2019. Measurement data with normal distribution were described as n Mean±n SD, and comparison between groups was analyzed using independent samples n t test or the matched samples n t test. Measurement data with skewed distribution were described as n M(range). Count data were represented as absolute numbers, and comparison between groups was analyzed using the chi-square test or Fisher exact probability. Univariate and multivariate analyses were conducted using the COX regressional model. Variables with n P<0.10 in the univariate analysis were included for the multivariate analysis. Survival rates were calculated using the Kaplan-Meier method, and Log-rank test was used for survival analysis.n Results:(1) The mtDNA copy number of tumor tissues and adjacent normal tissues and relationship between the mtDNA copy number and clinicopathological characteristics of HCC patients: of 71 HCC patients, the mtDNA copy number was 0.85±0.08 in tumor tissues, versus 1.16±0.08 in adjacent normal tissues, showing a significant difference between them (n t=2.96, n P<0.05). Of 71 HCC patients, 48 cases were mtDNA-low and 23 cases were mtDNA-high. Cases with tumor capsule as integrity or not-integrity, cases with or without microvascular (MVI) in mtDNA-low and mtDNA-high patients were 20, 28, 21, 27 and 16, 7, 4, 19, respectively, showing significant differences (n χ2=4.84, 4.74, n P<0.05). (2) Follow-up: 71 patients were followed up for 2.1 to 85.3 months, with a median follow-up time of 47.8 months. The 1-, 3-, 5-year overall survival rates of 71 HCC patients were 87.3%, 64.7, 37.4%, respectively. Moreover, the 1-, 3-, 5-year overall survival rates were 81.2%, 50.0%, 29.2% of the mtDNA-low patients, versus 95.7%, 86.5%, 54.7% of the mtDNA-high patients, showing a significant difference between the two groups (n χ2=5.86, n P<0.05). (3) Related factors for the prognosis of HCC patients. Results of univariate analysis showed that the number of tumor, portal vein tumor thrombus, MVI, Barcelona Clinic Liver Cancer stage, mtDNA copy number were related factors for the prognosis of HCC patients (n hazard ratios=2.211, 2.911, 3.899, 3.587, 0.440, 95% n confidence intervals as 1.024?4.777, 1.485?5.704, 2.115?7.186, 1.615?7.966, 0.223?0.871, n P<0.05). Results of multivariate analysis showed that MVI and mtDNA copy number were independent influencing factors for the prognosis of HCC patients (n hazard ratios=2.754, 0.437, 95% n confidence intervals as 1.374?5.521, 0.205?0.932, n P<0.05).n Conclusions:The mtDNA copy number of HCC patients is related with tumor capsule and MVI. The mtDNA copy number and MVI are independent influencing factors for the prognosis of HCC patients.
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