Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis
Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis
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DOI：
10.1016/s0002-9440(10)64123-5
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发表时间：
2001-05-01
影响因子：
6
通讯作者：
Hahn, SA
中科院分区：
文献类型：
--
作者：
Lüttges, J;Galehdari, H;Hahn, SA
胰腺导管腺癌的假定前体病变最近根据其不典型增生的逐渐增加的级别进行了分类，并被指定为胰腺上皮内瘤变 (PanIN) 1 至 3。在这项研究中，我测试了分子遗传改变是否与该分类相关，并可能有助于进一步对各种 PanIN 级别进行分类。我们结合全基因组扩增和微卫星分析，确定了不同 PanIN 级别的 81 个微解剖导管病变中染色体臂 9p、17p 和 18q 等位基因丢失的频率。此外，我们通过免疫组织化学分析检查了 p53 和 Dpc4 蛋白表达模式。在 PanLN-1 中，我们没有检测到等位基因丢失。在 PanIN-2 中，等位基因丢失的频率不断增加，在中度不典型增生的病变中尤其高（低度，分别为 20、33 和 17%，分别在 9p、17p 和 18q 处丢失；中度，46、77 和 58%），PanIN-3 和浸润性癌表现出丰富的丢失。 p53和Dpc4蛋白表达异常在PanIN-2病灶中很少被发现，但在PanIN-3病灶和浸润性癌中经常发生。综合遗传和蛋白表达数据支持这样一种模型，其中等位基因丢失是p53和DPC4抑癌基因双等位基因失活中的第一个打击。此外，我们的数据表明等位基因丢失分析可能有助于将具有低度不典型增生的PanIN-2病灶与具有低度不典型增生的PanIN-2病灶区分开来。中度不典型增生，每一种都可能代表着向浸润性癌的不同进展。
The presumed precursor lesions of pancreatic ductal adenocarcinoma were recently classified according to their increasing grade of dysplasia and were designated as pancreatic intraepithelial neoplasia (PanIN) 1 through 3, In this study, me tested whether molecular genetic alterations can be correlated with this classification and may help to further categorize the various PanIN grades. We determined the frequencies of allelic loss at chromosomal arms 9p, 17p, and 18q in 81 microdissected duct lesions of various PanIN grades, using a combination of whole genome amplification and microsatellite analysis. In addition we examined the p53 and Dpc4 protein expression patterns by immunohistochemical analysis. In PanLN-1, we did not detect allelic losses. In PanIN-2, allelic losses were found in increasing frequency, and were particularly high in those lesions with moderate-grade dysplasia (low grade, 20, 33, and 17%, loss at 9p, 17p, and 18q, respectively; moderate grade, 46, 77, and 58%), PanIN-3 and invasive carcinomas exhibited abundant losses. Abnormal p53 and Dpc4 protein expression was only rarely identified in PanIN-2 lesions, but occurred frequently in PanIN-3 lesions and invasive carcinomas, The combined genetic and protein expression data support a model in which allelic loss is the first hit in the biallelic inactivation of the p53 and DPC4 tumor suppressor genes, In addition, our data indicate that allelic loss analysis may be useful in separating PanIN-2 lesions with low-grade dysplasia from those PanIN-2 lesions with moderate-grade dysplasia, each potentially representing a distinct progression step toward invasive carcinoma.