通过线粒体DNA D-Loop区序列分析鉴别多结节性肝细胞性肝癌细胞克隆起源
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摘要
目的探讨线粒体DNA(mtDNA)D-Loop区序列分析结合临床病理因素判断多结节性肝细胞性肝癌(肝癌,HCC)细胞克隆起源的可行性。
方法分组:实验组为多结节肝癌组,来自广西医科大学第一附属医院肝胆外科2004年4月至2007年8月连续收治的42例共112个结节HCC的根治性手术切除肿瘤组织;对照组来自同期单结节HCC手术切除组织共20例40个样本,分两个亚组,对照组Ⅰ为16例单结节肝癌的2块不相邻的癌组织;对照组Ⅱ为4例伴有肉眼门静脉癌栓的肝癌患者,各取癌和癌栓1块。正常对照组来自同期肝移植供肝或肝外伤切除组织共5例。用PCR结合直接测序的方法检测各样本组织mtDNA D-Loop区的序列,并分析各例癌结节中序列异同情况。同时对相关的临床病理资料进行统计学处理。
结果实验组中有20例各结节的mtDNA D-Loop区序列存在差异,可能为多中心(MO)起源,22例各结节的mtDNA D-Loop区序列完全相同,可能为单中心(即肝内转移,IM)起源;对照组20例中各样本的mtDNA D-Loop区序列完全相同,为相同细胞克隆起源。HBeAg(P=0.008)、肿瘤大小(肿瘤直径之和)(P=0.029)、肿瘤分布(位置)(P=0.041)、肝硬化(P=0.011)、门静脉及镜下癌栓(P=0.023)、主瘤的病理分化程度(Edmondson病理分级)(P=0.026)等是区分多结节性肝癌细胞克隆起源的重要指标;HBeAg(+)、肿瘤直径之和≤7cm、肿瘤结节分别位于不同半肝、肝硬化、门静脉及镜下无癌栓和/或主瘤的病理分化程度为高、中分化者,MO发生的机率高。MO组无瘤生存时间(20.7±4.5个月)明显长于IM组的无瘤生存时间(6.3±1.3个月,P=0.022);MO组生存时间(29.1±4.4个月)明显长于IM组的生存时间(10.1±1.5个月,P=0.006)。在多因素分析中,IM/MO是无瘤生存时间(P=0.012)和生存时间(P=0.011)的独立影响因素。
结论1.在多结节性肝癌发生中,存在单中心性和多中心性两种不同的起源方式。mtDNA D-Loop区序列具有较高的变异率,应用PCR结合直接测序的方法检测该区序列并比较各个癌结节的DNA序列异同,可以快速、简单、有效地为区分IM和MO起源提供参考。2.HBeAg、肿瘤大小(肿瘤直径之和)、肿瘤分布(位置)、肝硬化、门静脉及镜下癌栓、主瘤的病理分化程度等是协助鉴别IM和MO起源的重要指标;HBeAg(+)、肿瘤直径之和≤7cm、肿瘤结节分别位于不同半肝、肝硬化、门静脉及镜下无癌栓和/或主瘤的病理分化程度为高、中分化者,MO发生的机率高。3.多中心性来源的肝癌疗效及预后较好。
Objective To explore the feasibility of identifying clonal origin of hepatocellular carcinoma(HCC)by analyzing the mitochondrial DNA D-Loop region variations and the clinicopathologic characteristics.
Methods Study group(multinodular HCCs)were 42 patients with a total of 112 HCC nodules who were consequentially hospitalized for radical resection of HCC in the department of hepatobiliary surgery of the first affiliated hospital to Guangxi medical university from April 2004 to August 2007.Controls were 20 HCCs(40 samples)hospitalized in the same period that consisted of two sub-groups:control groupⅠconsisted of 16 single nodular HCC cases that each had two pieces of inconsecutive tumor tissues and control groupⅡconsisted of 4 HCC cases with portal vein tumor embolus whose tumor tissues and portal vein tumor embolus were collected simultaneously.Normal control were 5 patients who were donors for liver transplantation or underwent liver trauma without any liver desease.Polymerase chain reaction(PCR)and direct sequencing were applied to study the mtDNA D-Loop region.The sequences were compared among multinodular lesions in study group,between inconsecutive tumor tissues and between tumor and embolus tissues in the control group with regard to their clinicopathologic characteristics.
Results In study group,20 cases were categorized as multicentric occurrence(MO)based on their variant mtDNA D-Loop sequences in each nodule from the same patient.And 22 cases were characterized as intrahepatic metastasis(IM)based on the identical mtDNA D-Loop sequences found in each nodule from the same patient.In all 20 cases in the control group,the inconsecutive tumor tissues or the portal vein tumor embolus and original tumors shared identical mtDNA D-Loop sequences.HBeAg(P=0.008),tumor size(sizes of all nodules)(P=0.029),position of nodules(P=0.041),cirrhosis (P=0.011),portal vein and microscope tumor embolus(P=0.023)and differentiation degree(Edmondson grade)of the main nodule(P=0.026)had the significant differences in the two original HCCs(IM and MO),and were considered to be the important factors in differentiating the cell clonal origin in multinodular HCC.Positive HBeAg,cumulative diameter of all nodules≤7cm, nodules located in different lobes,cirrhosis,without portal vein or microscope tumor embolus and/or well/moderate differentiation of main nodular histopathology were attributed to a high rate of MO.Tumor-free survival of the MO subjects(20.7±4.5 months)was significantly longer than that of the IM subjects(6.3±1.3 months,P=0.022).Similarly,overall survival of the MO subjects(29.1±4.4 months)was longer than that of the IM subjects(10.1±1.5 months,P=0.006).Multivariate analysis revealed that the IM/MO characteristic was an independent factor for either tumor-free survival(P=0.012)or overall survival(P=0.011).
Conclusions 1.There is a high rate of changes in mtDNA D-Loop region.And our study speculates a novel discrimination of MO and IM origins among multinodular HCCs using PCR and direct sequencing of the mtDNA D-Loop sequences.2.HBeAg,tumor size(sizes of all nodules),position of nodules,cirrhosis,portal vein and microscope tumor embolus and differentiation degree of the main nodule are the important factors to differentiate IM from MO.Positive HBeAg,cumulative diameter of all nodules ≤7cm,nodules located in different lobes,cirrhosis,without portal vein or microscope tumor embolus and/or well/moderate differentiation of main nodular histopathology are attributed to a high rate of MO.3.MO HCC patients might have a favorable outcome compared with IM patients.
方法分组:实验组为多结节肝癌组,来自广西医科大学第一附属医院肝胆外科2004年4月至2007年8月连续收治的42例共112个结节HCC的根治性手术切除肿瘤组织;对照组来自同期单结节HCC手术切除组织共20例40个样本,分两个亚组,对照组Ⅰ为16例单结节肝癌的2块不相邻的癌组织;对照组Ⅱ为4例伴有肉眼门静脉癌栓的肝癌患者,各取癌和癌栓1块。正常对照组来自同期肝移植供肝或肝外伤切除组织共5例。用PCR结合直接测序的方法检测各样本组织mtDNA D-Loop区的序列,并分析各例癌结节中序列异同情况。同时对相关的临床病理资料进行统计学处理。
结果实验组中有20例各结节的mtDNA D-Loop区序列存在差异,可能为多中心(MO)起源,22例各结节的mtDNA D-Loop区序列完全相同,可能为单中心(即肝内转移,IM)起源;对照组20例中各样本的mtDNA D-Loop区序列完全相同,为相同细胞克隆起源。HBeAg(P=0.008)、肿瘤大小(肿瘤直径之和)(P=0.029)、肿瘤分布(位置)(P=0.041)、肝硬化(P=0.011)、门静脉及镜下癌栓(P=0.023)、主瘤的病理分化程度(Edmondson病理分级)(P=0.026)等是区分多结节性肝癌细胞克隆起源的重要指标;HBeAg(+)、肿瘤直径之和≤7cm、肿瘤结节分别位于不同半肝、肝硬化、门静脉及镜下无癌栓和/或主瘤的病理分化程度为高、中分化者,MO发生的机率高。MO组无瘤生存时间(20.7±4.5个月)明显长于IM组的无瘤生存时间(6.3±1.3个月,P=0.022);MO组生存时间(29.1±4.4个月)明显长于IM组的生存时间(10.1±1.5个月,P=0.006)。在多因素分析中,IM/MO是无瘤生存时间(P=0.012)和生存时间(P=0.011)的独立影响因素。
结论1.在多结节性肝癌发生中,存在单中心性和多中心性两种不同的起源方式。mtDNA D-Loop区序列具有较高的变异率,应用PCR结合直接测序的方法检测该区序列并比较各个癌结节的DNA序列异同,可以快速、简单、有效地为区分IM和MO起源提供参考。2.HBeAg、肿瘤大小(肿瘤直径之和)、肿瘤分布(位置)、肝硬化、门静脉及镜下癌栓、主瘤的病理分化程度等是协助鉴别IM和MO起源的重要指标;HBeAg(+)、肿瘤直径之和≤7cm、肿瘤结节分别位于不同半肝、肝硬化、门静脉及镜下无癌栓和/或主瘤的病理分化程度为高、中分化者,MO发生的机率高。3.多中心性来源的肝癌疗效及预后较好。
Objective To explore the feasibility of identifying clonal origin of hepatocellular carcinoma(HCC)by analyzing the mitochondrial DNA D-Loop region variations and the clinicopathologic characteristics.
Methods Study group(multinodular HCCs)were 42 patients with a total of 112 HCC nodules who were consequentially hospitalized for radical resection of HCC in the department of hepatobiliary surgery of the first affiliated hospital to Guangxi medical university from April 2004 to August 2007.Controls were 20 HCCs(40 samples)hospitalized in the same period that consisted of two sub-groups:control groupⅠconsisted of 16 single nodular HCC cases that each had two pieces of inconsecutive tumor tissues and control groupⅡconsisted of 4 HCC cases with portal vein tumor embolus whose tumor tissues and portal vein tumor embolus were collected simultaneously.Normal control were 5 patients who were donors for liver transplantation or underwent liver trauma without any liver desease.Polymerase chain reaction(PCR)and direct sequencing were applied to study the mtDNA D-Loop region.The sequences were compared among multinodular lesions in study group,between inconsecutive tumor tissues and between tumor and embolus tissues in the control group with regard to their clinicopathologic characteristics.
Results In study group,20 cases were categorized as multicentric occurrence(MO)based on their variant mtDNA D-Loop sequences in each nodule from the same patient.And 22 cases were characterized as intrahepatic metastasis(IM)based on the identical mtDNA D-Loop sequences found in each nodule from the same patient.In all 20 cases in the control group,the inconsecutive tumor tissues or the portal vein tumor embolus and original tumors shared identical mtDNA D-Loop sequences.HBeAg(P=0.008),tumor size(sizes of all nodules)(P=0.029),position of nodules(P=0.041),cirrhosis (P=0.011),portal vein and microscope tumor embolus(P=0.023)and differentiation degree(Edmondson grade)of the main nodule(P=0.026)had the significant differences in the two original HCCs(IM and MO),and were considered to be the important factors in differentiating the cell clonal origin in multinodular HCC.Positive HBeAg,cumulative diameter of all nodules≤7cm, nodules located in different lobes,cirrhosis,without portal vein or microscope tumor embolus and/or well/moderate differentiation of main nodular histopathology were attributed to a high rate of MO.Tumor-free survival of the MO subjects(20.7±4.5 months)was significantly longer than that of the IM subjects(6.3±1.3 months,P=0.022).Similarly,overall survival of the MO subjects(29.1±4.4 months)was longer than that of the IM subjects(10.1±1.5 months,P=0.006).Multivariate analysis revealed that the IM/MO characteristic was an independent factor for either tumor-free survival(P=0.012)or overall survival(P=0.011).
Conclusions 1.There is a high rate of changes in mtDNA D-Loop region.And our study speculates a novel discrimination of MO and IM origins among multinodular HCCs using PCR and direct sequencing of the mtDNA D-Loop sequences.2.HBeAg,tumor size(sizes of all nodules),position of nodules,cirrhosis,portal vein and microscope tumor embolus and differentiation degree of the main nodule are the important factors to differentiate IM from MO.Positive HBeAg,cumulative diameter of all nodules ≤7cm,nodules located in different lobes,cirrhosis,without portal vein or microscope tumor embolus and/or well/moderate differentiation of main nodular histopathology are attributed to a high rate of MO.3.MO HCC patients might have a favorable outcome compared with IM patients.
引文
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