Molecular pathological analysis on the precancerous lesions and early changes in the multistep carcinogenesis of human stomach

本研究通过对胃癌前病变的分子病理学检查，阐明其在胃癌发生发展中的意义。肠化生黏膜中有P53蛋白阳性细胞，正常胃粘膜中无P53蛋白阳性细胞。PCR-SSCP和荧光原位氢化（FISH）显示，5例肠化生标本中有2例p53基因（外显子5和8）发生点突变，而基因缺失未得到证实。光镜和末端脱氧核苷酸转移酶介导的dutp -生物素缺口末端标记（TUNEL）显示凋亡细胞。它们分布在化生腺体的较深部分，靠近增生区，不完全型的频率高于完全型。c-ERBB2和c-ERBB3基因产物在化生黏膜中表达变化，提示其在增殖中的作用。45个胃管状腺瘤中存在不同程度的凋亡细胞，高级别非典型增生的腺瘤细胞凋亡频率显著高于低级别非典型增生的腺瘤细胞凋亡频率（p<0.05）。9例高分化胃癌细胞凋亡率为7.7 ~ 14.5%，5例低分化胃癌细胞凋亡率为2.7 ~ 7.5%，高分化胃癌细胞凋亡率显著高于低分化胃癌细胞凋亡率（p<0.01）。管状腺瘤中p53蛋白无免疫反应性，17号染色体和p53基因未见数值畸变。c-ERBB2和c-ERBB3基因产物在腺瘤中的免疫反应性较弱。这些结果表明p53基因在胃肠道化生中发生畸变。包括化生腺和管状腺瘤在内的癌前病变不同程度地含有凋亡细胞，凋亡细胞不仅在其形态发生中起关键作用，而且在肿瘤细胞的增殖中起关键作用。

This study was couducted to examine gastric precancerous lesions molecular pathologically to clarify their significance on the development of gastric cancers.P53 protein positive cells were noted in intestinal metaplastic mucosa, but not in normal gastric mucasa. PCR-SSCP and fluorescence in situ hydridization (FISH) revealed point mutation of p53 genes (exon 5 and 8) in two of the five specimens with intestinal metaplasia, while loss of the genes was not confirmed. Apoptotic cells were demonstrated by both light microscopy and terminal deoxynucleotidy1 transferase-mediated DUTP-biotin nick end labeling (TUNEL). They distributed in a deeper portion of the metaplastic glands, near proliferative zone, the frequency being higher in incomplete type than in complete type. Metaplastic mucosa expressed c-ERBB2 and c-ERBB3 gene product variably, suggesting the role of their proliferation.Forty-five gastric tubular adenomas contained apoptotic cells variably, the frequency being significantly (p<0.05) higher in the adenomas showing high grade dysplasia than those with low grade dysplasia. Apoptosis were detected from 7.7 to 14.5% of all gastric cancer cells in 9 well differentiated carcinomas, and from 2.7 to 7.5% in 5 poorly differentiated carcinomas, the frequency being significantly (p<0.01) higher in the former than in the latter. No immunoreactivity for p53 protein was demonstrated in the tubular adenoma, in which no numerical aberration of chromosome 17 and p53 gene was noted. Immunoreactivity for c-ERBB2 and c-ERBB3 gene products was weak in the adenomas.These results indicated that p53 gene aberration occurred in gastric intestinal metaplasia. Precancerous lesion including metaplastic glands and tubular adenomas variably contained apoptotic cells which play a crucial roles not only in their morphogenesis, but also in the proliferation of the tumor cells.