I m m u n o h i s t o c h e m i s t r y V e r s u s M i c r o s a t e l l i t e I n s t a b i l i t y T e s t i n g i n P h e n o t y p i n g C o l o r e c t a l T u m o r s
IHC in colorectal tumors for protein products hMLH1 and hMSH2 provides a rapid, cost-effective, sensitive (92.3%), and extremely specific (100%) method for screening for DNA mismatch repair defects. The predictive value of normal IHC for an MSS/MSI-L phenotype was 96.7%, and the predictive value of abnormal IHC was 100% for an MSI-H phenotype. Testing strategies must take into account acceptability of missing some cases of MSI-H tumors if only IHC is performed.
It is now generally recognized that a specific subset of those patients clinically defined as having hereditary non polyposis colon cancer (HNPCC) have germline mutations in any one of several genes involved in DNA mismatch repair (MMR). This important subset of HNPCC families is now defined as having Lynch syndrome. A considerable amount of data has shown that tumors from patients with Lynch syndrome have characteristic features resulting from the underlying molecular involvement of defective MMR, that is, the presence of microsatellite instability (MSI) and the absence of MMR protein expression by immunohistochemistry (IHC). As a result, identifying patients with Lynch syndrome can now be accomplished by testing tumors for these tumor-related changes. Together, MSI and IHC are powerful tools that help identify individuals at risk for having Lynch syndrome and to distinguish these cases from HNPCC cases with other hereditary gene defects. Furthermore, IHC analysis provides valuable clues as to which MMR gene is mutated, allowing for comprehensive mutational analyses of that gene. Here, we discuss the current and historical perspectives regarding MSI and IHC analyses in tumors from sporadic colon cancer and from patients with Lynch syndrome. Given this background, we also provide a testing strategy for the identification of patients at risk for Lynch syndrome and subsequent gene testing.
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