人肝癌中p16和CDK4基因的遗传变异及其与HBV感染之间的关系

The genetic alteration of p16 and CDK4 genes and their relations to HBV infection in human hepatocellular carcinoma

目的探讨抑癌基因ｐ１６和癌基因ＣＤＫ４的遗传变异在人肝癌发生发展中的作用及其相互关系以及与ＨＢＶ感染之间的关系。方法取手术切除的肝癌标本，用Ｓｏｕｔｈｅｒｎ杂交法对ｐ１６和ＣＤＫ４基因以及ＨＢＶ的状态进行检测，同时切片行病理检查。结果３６例肝癌中４例有ｐ１６纯合性缺失，３例半合子丢失，总丢失率为１９．４％，其中约１／３的ｐ１６丢失发生在肿瘤小于５ｃｍ的肝癌；在有ＨＢＶ－ＤＮＡ整合和无整合的病例中，ｐ１６的丢失率差异无显著性。３７例肝癌中５例（１３．２％）发生ＣＤＫ４扩增，与ｐ１６的丢失无重叠；ＣＤＫ４的扩增全部发生在有ＨＢＶ整合的肝癌中。结论ｐ１６的丢失在部分肝癌的发生发展中起着一定的作用，但与ＨＢＶ－ＤＮＡ的整合无关；ＣＤＫ４的扩增可能与ＨＢＶ－ＤＮＡ的整合以及肝癌的进展有关。

Objective To explore the genetic alterations of the tumor suppressor gene p16 and oncogene CDK4,as well as their relations to HBV infection during the developmental process of human hepatocellular carcinoma (HCC).Methods 40 cases of fresh paired tumor and nontumor liver tissues obtained from surgical resections were used for genetic analysis of p16,CDK4 and HBV DNA with Southern blot and hybridization. These samples were also examined histologically.Results The homozygous deletions of p16 gene were detected in 4 of 36 cases and hemizygous deletions in another 3 cases. The frequency of p16 deletion was 19.4%.About one third of p16 deletion was found in HCCs with tumor size<5cm.The deletion of p16 was not correlated with the integration of HBV DNA.CDK4 amplifications were detected in 5 of 37 cases (13.2%),and the gene amplifications and p16 deletions did not appear in the same case. All of the cases with CDK4 amplifications were detected in the HCCs with HBV DNA integration. The majority of amplifications were observed in HCCs with poorer differentiation, higher index of mitosis and larger size.Conclusion p16 deletion might play certain important role in a subset of HCCs and didn’t correlate with the HBV DNA integration;CDK4 amplification could be correlated with HBV DNA integration and the progression of HCC.