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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 heterozygosity (LOH) and microsatellite instability (MSI) of tumor suppressor gene (TSG) in the pathogenesis of hepatocellular carcinoma and to explore its clinicopathological significance. Methods Thirty-six patients with hepatocellular carcinoma (HCC) were screened from 92 patients with hepatocellular carcinoma (TSC) by direct DNA sequencing. Six TSGs (APC, DCC, MCC, OGG1, p53 and RB1) LOH, and 13 polymorphic microsatellite loci were detected by LOH and MSI in 15 cases of hepatocellular carcinoma, and their correlations with clinicopathological parameters were statistically analyzed. Results The total incidence of LOH in TSG was 41.7% (15/36), and no LOH was observed in only MCC gene. Microsatellite LOH occurred in 9 of 15 (60%) hepatocellular carcinomas, accounting for 46.2% (6/13) of the detected microsatellites, but none of them showed MSI. When the LOH of APC, OGG1 and DCC were type Ⅰ (n = 7) and the p53 and RB1 gene LOH were type Ⅱ (n = 8), the mean tumor diameters of the two groups of hepatocellular carcinoma were (2. 9 ± 1 .7) cm and (7.2 ± 3.4 cm), respectively (P <0.01). The average postoperative survival time was (72. 0 ± 38 6) months and (51.0 ± 30.4) months (P <0 .05). There was no significant correlation between HCC gene variants and patient’s age, sex, serum alpha-fetoprotein level, HBsAg positive rate, combined hepatitis / cirrhosis, hepatocellular carcinoma differentiation and histological type. Conclusion LOH pathway plays a greater role than MSI pathway in the multi-stage evolution and multi-gene variation of hepatocellular carcinoma. Type Ⅰ gene mutations (APC, OGG1 and DCC) mainly in the early stages of liver cancer?