Günther T, Schneider-Stock R, Häckel C, Kasper H U, Pross M, Hackelsberger A, Lippert H, Roessner A
Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany.
Mod Pathol. 2000 Jun;13(6):621-6. doi: 10.1038/modpathol.3880107.
Mdm2, localized on chromosome 12, is considered a negative regulator of p53 function and seems to play a role in the pathogenesis of a variety of tumors. The mdm2 amplification in advanced-stage gastric carcinoma has not yet been investigated. Mdm2 amplification was determined in 43 gastric carcinomas, and the genetic results were correlated with mdm2 protein expression, p53 alterations, and clinicopathologic data. The tumors were classified according to Lauren: 20 intestinal-type tumors, 19 tumors of diffuse growth inclusive of a primary small cell carcinoma, and 4 carcinomas with mixed differentiation. Staging was based on the pTNM classification system. Mdm2 and p53 were demonstrated by immunohistology on formalin-fixed and paraffin-embedded tumor tissue. The mdm2 oncogene was amplified by nonradioactive hybridization of tumor DNA with an mdm2 cDNA probe. The Southern blots were evaluated densitometrically. For p53 mutation screening, we analyzed the highly conservative regions of the p53 gene (exons 4 to 8) with the use of the polymerase chain reaction-single-strand conformation polymorphism technique. Polymerase chain reaction products with band shifting were directly sequenced. Mdm2 amplification was demonstrated in 18 tumors (41.8%). The mdm2 gene was amplified more frequently in carcinomas with a diffuse growth pattern. Gastric carcinomas of the intestinal type, however, showed a higher frequency of p53 alterations. There was no statistical significance of the molecular genetic and immunohistologic results of the mdm2/p53 status to staging as well as to age and sex of the patients. The mdm2/p53 pathway is a part of the carcinogenesis of gastric carcinoma. Only approximately 20% of gastric carcinomas failed to show mdm2 and/or p53 alterations. The upregulation of the mdm2 oncogene and the accompanying inactivation of the tumor suppressor gene 53 seem to play a role above all in carcinomas of the diffuse type.
定位于12号染色体的Mdm2被认为是p53功能的负调节因子，似乎在多种肿瘤的发病机制中起作用。晚期胃癌中mdm2基因扩增情况尚未见研究报道。本研究检测了43例胃癌组织中的mdm2基因扩增情况，并将基因检测结果与mdm2蛋白表达、p53改变及临床病理资料进行相关性分析。肿瘤按Lauren分类：肠型20例，弥漫生长型19例（包括1例原发性小细胞癌），混合分化型4例。分期依据pTNM分类系统。采用免疫组织化学方法检测福尔马林固定、石蜡包埋的肿瘤组织中Mdm2和p53的表达。采用非放射性杂交技术，以mdm2 cDNA探针检测肿瘤DNA中mdm2癌基因的扩增情况。对Southern杂交结果进行光密度分析。采用聚合酶链反应-单链构象多态性技术分析p53基因高度保守区（外显子4至8），对出现条带迁移的聚合酶链反应产物直接测序。结果显示，18例肿瘤（41.8%）存在mdm2基因扩增。mdm2基因在弥漫生长型胃癌中扩增更为常见。然而，肠型胃癌中p53改变更为常见。mdm2/p53状态的分子遗传学及免疫组化结果与肿瘤分期、患者年龄及性别之间无统计学差异。mdm2/p53信号通路是胃癌发生机制的一部分。仅约20%的胃癌未出现mdm2和/或p53改变。mdm2癌基因的上调及伴随的肿瘤抑制基因p53失活似乎在弥漫型胃癌中起主要作用。
