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Inactivation of smad4 occurs in 55% of pancreatic cancers and approximately 15% of colorectal cancers, usually by a combination of mutation and allelic deletion.
Recently, an immunohistochemical marker has been developed for assessment of smad4 expression in formalin-fixed tissues, which closely mirrors the genetic status of smad4 gene. Smad4 expression in pancreatic adenocarcinomas by immunohistochemistry has greater than 90% correlation with the presence of genetic alterations in the smad4 gene; in addition the use of immunohistochemical analysis has shown down regulation of smad4 in a subset of precursor lesions of pancreatic cancer called pancreatic intraepithelial neoplasia or PanIN. In contrast to the high frequency of loss of expression in conventional ductal adenocarcinomas, the majority of intraductal papillary neoplasms of the pancreas retain smad4 expression. Similarly, within the group of mucinous cystic neoplasms, frequent loss of smad4 expression is seen only in the invasive cancers, suggesting a role for this protein in the genetic progression of these tumors. In colorectal cancers, loss of smad4 protein occurs late in tumorigenesis, and shows a weak correlation with the presence of metatstatic disease.
Veripath OncoDiagnostics offers smad-4 immunohistochemical analysis on routinely fixed archival tissue specimens. The antibody is optimally used in formalin fixed material; most other fixatives such as B-5 yield suboptimal results. Currently, we are using an automated image analysis system to quantitatively score percentage positivity and intensity grade for smad4 finally reflected in a histoscore on each evaluation. The smad4 analysis is routinely offered as part of the pancreatic tumor panel, but can be ordered for individual tumor types as well. For more information contact Dr Raheela Ashfaq at Veripath OncoDiagnostics at 214.645.7053 or Raheela.Ashfaq@UTSouthwestern.edu.
Selected references:
1. Iacobuzio-Donahue CA et al. Dpc4 protein in mucinous cystic neoplasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol 24:1544; 2000
2. Maitra A et al. Loss of Dpc4 expression in colonic adenocarcinomas correlates with the presence of metastatic disease. Am J Pathol 157:1105; 2000.
3. Wilentz RE et al. Immunohistochemical labeling for Dpc4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation.
4. Wilentz RE et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 60:2002; 2000
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