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Mutations or allelic deletions of the APC gene are present in nearly 80% of sporadic colorectal carcinomas, and a similar proportion of adenomas. Recent investigations have revealed a third mechanism of gene inactivation, involving hypermethylation of the APC promoter region. Loss of APC function is one of the earliest events in colorectal carcinogenesis and can be detected even at the stage of aberrant crypt foci. In addition to colorectal cancers, somatic mutations of APC have been described in other gastrointestinal tumors, including gastric, pancreatic, esophageal and hepatocellular carcinomas. With the existing methodologies of detection, mutations of the APC gene are quite uncommon in sporadic extra-gastrointestinal tumors such as breast and lung cancers.
An immunohistochemical antibody for assessment of APC protein expression has been developed, and is applicable to routinely fixed archival tissues. The APC protein has a diffuse cytoplasmic distribution, although rarely, it may demonstrate nuclear localization. Like all immunohistochemical assays, this technique has the advantage of detecting APC status irrespective of the mechanism of gene inactivation. For example, a recent study has shown that nearly 40% of breast carcinomas demonstrate reduction or loss of APC expression, despite the low frequency of somatic gene mutations in this tumor. As the importance of epigenetic mechanisms of inactivation - primarily through promoter hypermethylation - becomes increasingly manifest in human neoplasia, immunohistochemical assessment of APC expression may offer the best and quickest alternative to circumvent the need for detailed genetic analysis.
Veripath OncoDiagnostics offers APC as part of the standard esophagus, stomach and colorectal cancer panels, but it can also be ordered individually. Currently, we are using an automated image analysis system to quantitatively score percentage positivity and intensity grade for APC finally reflected in a histoscore on each evaluation. For more information contact Dr Raheela Ashfaq at 214.645.7026 or Raheela.Ashfaq@UTSouthwestern.edu.
Selected references:
1. Akehi S et al. Immunohistochemical detection of truncated APC protein in sporadic human colorectal adenomas and adenocarcinomas. Virchows Arch 429:21; 1996
2. Esteller M et al. Analysis of the adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res 60:4366; 2000
3. Ho et al. Reduced expression of APC and DCC gene protein in breast cancer. Histopathology 35:249; 1999
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