Sakai Y, Yanagisawa A, Shimada M, Hidaka E, Seki M, Tada Y, Harada T, Saisho H, Kato Y
Department of Pathology, Cancer Institute Hospital, Tokyo, Japan.
Hum Pathol. 2000 Jul;31(7):795-803. doi: 10.1053/hupa.2000.8442.
Mucin-producing tumors (MPTs) of the pancreas accompanied by carcinomas usually include various grades of dysplasia in the ductal epithelium, and invasive areas are histologically similar to those of common invasive ductal carcinomas, suggesting that MPTs provide a good tool to investigate early stages of pancreatic carcinogenesis. Thus, to clarify genetic alterations in the early stage of pancreatic carcinogenesis, we analyzed K-ras gene mutations and loss of heterozygosity (LOH) at the p53 gene locus using 37 cases of MPTs harboring dysplastic epithelium. Further, we conducted an extended, multifocal microdissection analysis focusing on the histological features of ductal epithelium and the distribution of genetic alterations for 3 cases of MPT positive for LOH of the p53 gene to determine the relation to tumor progression. K-ras gene mutations were detected with high frequency in 50% or more cases of the adenomas (14 of 19), borderline tumors (4 of 7), and carcinomas (8 of 11), whereas LOH of the p53 gene was limited to carcinomas (3 of 5 informative cases, 60%) and always accompanied by K-ras gene mutation. Investigation of a total of 126 microdissection sites from 3 cases showed the presence of K-ras gene mutations in mild dysplasia and all (100%) regions of moderate or more marked dysplasia, whereas LOH of the p53 gene showed more gradual tendency to increase with grade from moderate dysplasia. In addition, the multifocal genetic analysis showed K-ras gene mutations to be widely distributed throughout tumors, whereas LOH of the p53 gene was localized to 1 or a few areas. Further, topographically delimited areas with the same histology in the same tumor did not always show the same genetic alteration. In conclusion, we could confirm that both the K-ras and p53 gene alterations occur in the intraductal stage of MPT, and the latter is superimposed on the former during the course of tumor progression. However, the pattern of association of histological features with genetic alteration differs from tumor to tumor.
伴有癌的胰腺黏液产生性肿瘤（MPTs）通常在导管上皮中包括不同程度的发育异常，并且浸润区域在组织学上与常见浸润性导管癌相似，这表明MPTs为研究胰腺癌发生的早期阶段提供了一个良好的工具。因此，为了阐明胰腺癌发生早期的基因改变，我们使用37例具有发育异常上皮的MPTs分析了K-ras基因突变和p53基因位点的杂合性缺失（LOH）。此外，我们对3例p53基因LOH阳性的MPTs进行了扩展的多灶性显微切割分析，重点关注导管上皮的组织学特征和基因改变的分布，以确定其与肿瘤进展的关系。K-ras基因突变在50%或更多的腺瘤（19例中的14例）、交界性肿瘤（7例中的4例）和癌（11例中的8例）中高频检测到，而p53基因的LOH仅限于癌（5例信息性病例中的3例，60%），并且总是伴有K-ras基因突变。对3例共126个显微切割位点的研究表明，轻度发育异常以及中度或更明显发育异常的所有区域（100%）均存在K-ras基因突变，而p53基因的LOH从中度发育异常开始随分级增加呈现出更逐渐上升的趋势。此外，多灶性基因分析显示K-ras基因突变广泛分布于整个肿瘤，而p53基因的LOH局限于1个或几个区域。此外，同一肿瘤中具有相同组织学的地形界定区域并不总是显示相同的基因改变。总之，我们可以证实K-ras和p53基因改变均发生在MPT的导管内阶段，并且后者在肿瘤进展过程中叠加于前者之上。然而，组织学特征与基因改变的关联模式因肿瘤而异。
