肝细胞癌肿瘤抑制基因的杂合性缺失和微卫星不稳定性研究  

Study on loss of heterozygosity and microsatellite instability in hepatocellular carcinoma

作　　者：丛文铭[1] 张树辉[1] 冼志红[1] 吴伟清[1] 吴孟超[1] 

机构地区：[1]第二军医大学东方肝胆外科医院病理科,上海200438

出　　处：《中华病理学杂志》2005年第2期71-74,共4页Chinese Journal of Pathology

基　　金：上海市卫生系统"百人计划"项目资助(98BR007)

摘　　要：目的　了解肿瘤抑制基因(TSG)杂合性缺失(LOH)与微卫星不稳定性(MSI)在肝细胞癌发生机制中的作用,并探讨其临床病理学意义。方法　采用显微组织切割基础上的DNA直接测序法,从92例手术切除肝细胞癌中筛选出36例信息性肝细胞癌进行6种TSG(APC、DCC、MCC、OGG1、p53和RB1)的LOH检测,对其中15例肝细胞癌进行13个多态性微卫星位点的LOH和MSI检测,并与临床病理学参数的相关性进行统计学分析。结果　TSG的LOH总发生率为41 .7% (15 /36),仅MCC基因未出现LOH。15例肝细胞癌中有9例(60% )发生微卫星LOH,占检测微卫星的46 .2% (6 /13),但无1例肝细胞癌出现MSI。若将APC、OGG1和DCC基因LOH作为Ⅰ型(n=7 ),将p53和RB1基因LOH作为Ⅱ型(n=8)进行统计学处理,则两组肝细胞癌的平均瘤体直径分别为( 2. 9 ±1 .7)cm和(7 .2 ±3 .4)cm (P<0 .01),两组患者术后平均生存期分别为( 72. 0 ±38 6 )个月和(51 .0±30. 4)个月(P<0 .05 )。肝细胞癌基因变异型与患者的年龄、性别、血清甲胎蛋白水平、HBsAg阳性率、合并肝炎/肝硬化、肝细胞癌分化程度和组织学类型之间无明显相关性。结论　在肝细胞癌发生的多阶段演进与多基因变异过程中,LOH路径所起的作用要比MSI路径更大。Ⅰ型基因变异(APC、OGG1和DCC)主要在肝细胞癌早期阶段起作?Objective To investigate the role of loss of heterozygosity (LOH) in tumor suppressor genes (TSG) and microsatellite instability (MSI) in hepatocarcinogenesis, as well as their correlation with clinicopathologic features. Methods LOH in 6 TSG (APC, DCC, MCC, OGG1, p53 and RB1) was detected in 36 informative cases of hepatocellular carcinoma (HCC), among 92 surgically resected HCC. Thirteen polymorphic microsatellite markers were also studied in 15 of these cases by microdissection-based PCR amplification and direct DNA sequencing. The correlation between genetic alterations and clinicopathologic features was analyzed. Results The overall incidence of LOH in HCC was 41.7% (15/36). There was no LOH in MCC gene. 46.2% (6/13) microsatellites showed LOH in 9 of the 15 cases of HCC (60%). Certain clinicopathologic differences were observed between cases (number = 7) with LOH in APC, OGG1 and DCC (“type I) and cases (number = 8) with LOH in p53 and RB1 (“type II). The mean tumor size of these two types was 2.9 (± 1.7) cm and 7.2 (± 3.4) cm, respectively (P<0.01); and the mean survival was 72.0 (± 38.6) months, and 51.0 (± 30.4) months, respectively (P<0.05). Conclusions Compared with MSI pathway, LOH pathway plays a more important role in the development of HCC. A multistep hepatocarcinogenesis is likely, with LOH in APC, OGG1 and DCC (“type I”) being an early event and LOH in p53 and RB1 (“type Ⅱ”) being a late event. On the other hand, MCC gene seems to play no role in the whole process.

关 键 词：肝细胞癌 LOH 癌发生 杂合性缺失 微卫星不稳定性 癌肿瘤 患者 结论 阶段 信息性 

分 类 号：R735.7[医药卫生—肿瘤] R730[医药卫生—临床医学]