Ranzani G N, Luinetti O, Padovan L S, Calistri D, Renault B, Burrel M, Amadori D, Fiocca R, Solcia E
Department of Genetics and Microbiology, University of Pavia, Italy.
Cancer Epidemiol Biomarkers Prev. 1995 Apr-May;4(3):223-31.
We screened for p53 alterations in 71 early gastric cancers of differing histological types and growth patterns, 18 advanced cancers of diffuse type, 19 dysplastic lesions, and 12 extensive intestinal metaplasia cases. Tumors were investigated for gene mutations (exons 5-8) with PCR-based denaturing gradient gel electrophoresis and sequencing techniques, and for protein accumulation with immunohistochemical methods. Nontumor samples were studied with immunohistochemistry alone. Of the early cancers, intestinal tumors showed a much higher p53 mutation frequency (41%) than did diffuse cancers (4%). When comparing early and advanced tumors of the same type, we observed a similarity in mutation frequency (41 versus about 50%) for intestinal tumors, and a significant increase for diffuse tumors (from 4 to 33%). Immunopositive case distribution between tumor types and stages paralleled that of mutated cases. Immunohistochemical and genetic analysis gave concordant results for all samples with gene mutations. Eighteen of the 65 (28%) nonmutated tumors displayed significant immunoreactivity. Early tumors that massively penetrated the submucosa, i.e., the early tumors for which prognosis is worst, showed the highest frequency both of p53 gene mutation and of nonmutated protein accumulation. Twelve of 19 dysplastic lesions showed significant immunoreactivity, whereas intestinal metaplasias proved unreactive in all but a few cells. Our results yield two implications: that p53 alterations have a crucial and early role in gastric carcinogenesis of intestinal type, likely acting at the transition step between metaplasia and dysplasia; and that the alterations are mainly associated with tumor progression in cancer of diffuse type.
我们对71例不同组织学类型和生长模式的早期胃癌、18例弥漫型进展期癌、19例发育异常病变以及12例广泛肠化生病例进行了p53改变的筛查。采用基于聚合酶链反应的变性梯度凝胶电泳和测序技术研究肿瘤的基因突变（第5 - 8外显子），并用免疫组化方法研究蛋白质蓄积情况。非肿瘤样本仅用免疫组化进行研究。在早期癌症中，肠型肿瘤的p53突变频率（41%）远高于弥漫型癌症（4%）。在比较相同类型的早期和进展期肿瘤时，我们观察到肠型肿瘤的突变频率相似（41%对约50%），而弥漫型肿瘤则显著增加（从4%增至33%）。肿瘤类型和分期之间免疫阳性病例分布与突变病例相似。免疫组化和基因分析对所有基因突变样本的结果一致。65例（28%）未突变肿瘤中有18例显示出明显的免疫反应性。大量浸润黏膜下层的早期肿瘤，即预后最差的早期肿瘤，p53基因突变频率和未突变蛋白蓄积频率均最高。19例发育异常病变中有12例显示出明显的免疫反应性，而肠化生除少数细胞外均无反应。我们的结果有两点启示：p53改变在肠型胃癌发生过程中起关键的早期作用，可能作用于化生和发育异常之间的转变阶段；并且这些改变主要与弥漫型癌症的肿瘤进展相关。
