Dpc-4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas - Comparison with conventional ductal adenocarcinomas
Dpc-4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas - Comparison with conventional ductal adenocarcinomas
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DOI：
10.1016/s0002-9440(10)64589-0
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发表时间：
2000-09-01
影响因子：
6
通讯作者：
Hruban, RH
中科院分区：
文献类型：
--
作者：
Iacobuzio-Donahue, CA;Klimstra, DS;Hruban, RH
DPC4(MADH4，Smad4)编码一种核转录因子，在超过一半的传统胰腺浸润性导管腺癌中被证明是基因失活的，胰腺导管内乳头状黏液性肿瘤(IPMN)被认为是不同的肿瘤，其侵袭性明显低于传统的胰腺导管腺癌，但这些肿瘤类型的分子比较受到技术困难的影响。最近，DPC4基因产物的免疫组织化学标记被证明是胰腺癌中DPC4基因改变的一个极其敏感和特异的标记物。因此，我们使用一种已鉴定的单抗分析了79个IPMN中DPC4蛋白的免疫组织化学表达。29个IPMN中也有相关的浸润性腺癌可供分析。观察到的标记模式与我们之前报道的传统导管癌的标记模式进行了比较。IPMN的79个导管内成分均强表达DPC4蛋白。在79例中，77例(97%)标记为弥漫性阳性，2例(3%)为局灶性阳性。在29例浸润性癌中，28例(97%)表达DPC4。1例浸润性癌表现为DPC4表达缺失，与导管内的一个成分有关，后者表现为灶性缺失DPC4表达。DPC4在IPMN中的强且几乎普遍的表达与约30%的胰腺原位腺癌(所谓的胰腺上皮内肿瘤，3级；P<；0.001)和55%的胰腺导管癌(P<；0.0001)中DPC4的表达缺失形成鲜明对比。IPMN和导管癌之间DPC4表达的差异提示在肿瘤发生上存在根本的遗传差异，这可能与观察到的IPMN显著更好的临床结果有关。
DPC4 (MADH4, SMAD4) encodes a nuclear transcription factor shown to be genetically inactivated in over one-half of conventional infiltrating ductal adenocarcinomas of the pancreas, Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have been suggested to be distinct neoplasms with a significantly less aggressive course than conventional ductal adenocarcinomas of the pancreas, but molecular comparisons of these tumor types have previously been impaired by technical difficulties. Recently, immunohistochemical labeling for the DPC4 gene product has been shown to be an extremely sensitive and specific marker for DPC4 gene alterations in pancreatic adenocarcinomas. Therefore, we analyzed the immunohistochemical expression of Dpc4 protein in 79 IPMNs using a previously characterized monoclonal antibody. Twenty-nine of the IPMNs also had an associated infiltrating adenocarcinoma available for analysis. The labeling patterns observed were compared to those we have previously reported for conventional ductal carcinomas. All 79 of the intraductal components of the IPMNs strongly expressed Dpc4 protein. In 77 of the 79 cases (97%), the labeling was diffusely positive, and in 2 of the 79 (3%) the labeling was focally positive. Dpc4 expression was seen in 28 (97%) of the associated 29 invasive cancers. The one infiltrating carcinoma that showed loss of Dpc4 expression was associated with an Intraductal component which showed focal loss of Dpc4 expression. The strong and almost universal expression of Dpc4 in IPMNs contrasts sharply with the loss of Dpc4 expression seen in approximately 30% of in situ adenocarcinomas of the pancreas (so-called pancreatic intraepithelial neoplasms, grade 3; P < 0.001) and in 55% of pancreatic duct carcinomas (P < 0.0001). Differences in Dpc4 expression between IPMNs and ductal carcinomas suggest a fundamental genetic difference in tumorigenesis, which may relate to the significantly better clinical outcomes observed for IPMNs.