Yasui W, Yokozaki H, Fujimoto J, Naka K, Kuniyasu H, Tahara E
First Department of Pathology, Hiroshima University School of Medicine, Japan.
J Gastroenterol. 2000;35 Suppl 12:111-5.
An accumulation of multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, cell adhesion molecules, and the growth factor/receptor system is involved in the course of multistep conversion of normal epithelial cells to clinical gastric cancer. Some of them differ depending on the histological type, well-differentiated (intestinal) and poorly differentiated (diffuse) types, suggesting the presence of two distinct genetic pathways. Genetic instability, chromosomal instability (telomere reduction), and immortality (activation of telomerase and expression of telomerase reverse transcriptase: TERT) participate in the initial step of stomach carcinogenesis. Because TERT protein expression precedes the telomerase activities in precancerous lesions, TERT expression may be a prerequisite for telomerase activation. The cyclin E gene is amplified in 15%-20% of gastric cancer. Reduced expression of a cyclin-dependent kinase (CDK) inhibitor, p27Kip1, is frequently found in gastric cancer associated with high grade malignancy. E2F-1, an important downstream target of cyclins/CDKs, is overexpressed in about 40% of gastric carcinomas, whereas gene amplification of E2F-1 rarely occurs. Loss of heterozygosity (LOH) of p73, the p53-related new tumor suppressor gene, preferentially occurs in well-differentiated adenocarcinomas of foveolar type expressing pS2, a gastric-specific trefoil factor, indicating the importance of p73 LOH in the genesis.
原癌基因、肿瘤抑制基因、DNA修复基因、细胞周期调节因子、细胞黏附分子以及生长因子/受体系统的多种基因和表观遗传改变的积累参与了正常上皮细胞向临床胃癌的多步骤转变过程。其中一些改变因组织学类型而异，即高分化（肠型）和低分化（弥漫型）类型，这表明存在两条不同的遗传途径。遗传不稳定性、染色体不稳定性（端粒缩短）和永生化（端粒酶激活和端粒酶逆转录酶：TERT表达）参与胃癌发生的起始步骤。由于TERT蛋白表达先于癌前病变中的端粒酶活性，TERT表达可能是端粒酶激活的先决条件。细胞周期蛋白E基因在15%-20%的胃癌中发生扩增。细胞周期蛋白依赖性激酶（CDK）抑制剂p27Kip1的表达降低在与高恶性程度相关的胃癌中经常出现。细胞周期蛋白/CDK的重要下游靶点E2F-1在约40%的胃癌中过表达，而E2F-1的基因扩增很少发生。p73是一种与p53相关的新肿瘤抑制基因，其杂合性缺失（LOH）优先发生在表达胃特异性三叶因子pS2的小凹型高分化腺癌中，这表明p73 LOH在肿瘤发生中的重要性。
