胃癌组织中多种癌基因变异的观察

Correlation of multiple gene changes with malignant phenotype of human gastric carcinoma

目的 探索胃癌癌变过程中多种癌基因和抑癌基因变异的规律。方法用Ｓｏｕｔｈｅｒｎ杂交、ＰＣＲ／ＳＳＣＰ和ＤＮＡ测序技术，检测３３例胃癌手术标本中原癌基因ｃ－ｍｅｔ、ＥＧＦＲ、ｃ－Ｈａ－ｒａｓ、ｃ－ｅｒｂＢ－２、ＡＫＴ-２的扩增和重排，以及抑癌基因ｐ５３、ｐ１６、ｎｍ２３－Ｈ１的突变和缺失。结果大多数胃癌组织（７０％）存在１个或１个以上的基因改变。不同个体基因异常的种类和方式不同。其中ｃ－ｍｅｔ基因重排２／３３例（６％），扩增８／３３例（２４％）。ｃ－ｅｒｂＢ－２扩增１／３３（３％），ＡＫＴ－２扩增２／１８例（１１％）。抑癌基因ｐ１６的纯合性缺失６／３３例（１８％），ｎｍ２３－Ｈ１和ｐ５３的杂合性缺失分别是５／１７例（２９％）和２／１３例（１６％）。ｐ５３第５～８外显子点突变的检出率为２０／３３例（６１％）。癌基因的扩增和重排多发生于胃癌进展期，而ｐ５３基因的点突变可发生于癌变各期。结论胃癌癌变是多基因异常累积所引起的渐进性过程，基因改变的数目、种类及方式与肿瘤的恶性表型密切相关。

Objective To investigate the alteration of oncogenes and tumor suppressor genes in gastric carcino- genesis. Methods Southern blot , PCR /SSCP and DNA sequencing techniques were used in 33 gastric carcinomas to detect c-met , EGFR , c-erbB-2 , AKT-2 , c-Ha-ras , p53 , p1 6 and nm23-H1 , for the presence of amplification , deletion , mutation and rearrangement . Resul ts Most tumors ( 7 0 % ) haboured one or more altered genes. The number and type of gene alteration were different among indi- viduals. Rearrangement of c-met was noted in 2/33 cases ( 6 % ) , and amplification of c-met , c-erbB-2 and AKT-2 in 8/33 cases (24. 2%) , 1/33 cases (3%) and 2/18 cases (11%) respectively. Homozy- gous deletion of P16 was seen in 6/33 cases (18% ). Loss of heterosygousity was also noted in nm23-H1 5/17 (29%) and p53 2/13 (16%). The mutation rate of p53 in exon 5-8 was 20/33(61%). Point mu- tation of p5 3 was found at both early and advanced tumocs. In contrast , amplification of oncogenes and loss of tumor suppressor genes were correlated with poorly differentiated and metastatic tumors. Cooclu- slons Gastric carcinogenesis is a gradually developed process , results from sequencial alteration of multigenes. The malignant phenotype is associated with the degree of genetic abnormality.