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Published on: July 28, 2010
Immunohistochemistry for MSH2 and MHL1: a method for identifying mismatch repair deficient colorectal cancer
J G Stone1, D Robertson, R S Houlston
1Section of Cancer Genetics, Institute of Cancer Genetics, Sutton, Surrey ,UK.
Abstract:
Colorectal cancers with DNA mismatch repair (MMR) gene mutations characteristically display a high rate of replication errors in simple repetitive sequences detectable as microsatellite instability (MSI). Most are the result of somatic MMR dysfunction; however, a subset are caused by germline mutations. The availability of commercial antibodies for MSH2 and MLH1 [corrected] offers an alternative strategy to molecular methods for identifying MMR deficient cancers. To evaluate immunohistochemistry, MLH1 and MSH2 expression was studied using monoclonal antibodies in formalin fixed, paraffin wax embedded cancers. The immunohistochemical staining patterns of 23 cancers displaying MSI, including four cases with germline mutations, were compared with 23 microsatellite stable (MSS) cancers. All MSS cancers exhibited staining with both antibodies. Twenty two of the MSI cases showed absent MMR expression with either anti-MSH2 or anti-MLH1 [corrected]. The high sensitivity and predictive value of immunohistochemistry in detecting MMR deficiency offers a method of discriminating between MSI and MSS cancers caused by MSH2 and MLH1 [corrected] dysfunction. The application and suitability of immunohistochemistry for the detection of MSI and as a strategy for prioritising the mutational analysis of MMR genes in routine clinical practice is discussed.
Insights
Immunohistochemistry effectively identifies DNA mismatch repair (MMR) deficiency in colorectal cancers by detecting MSH2 and MLH1 protein loss. This method accurately distinguishes microsatellite instability (MSI) from microsatellite stable (MSS) tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Colorectal cancers with DNA mismatch repair (MMR) gene mutations exhibit microsatellite instability (MSI).
- MMR deficiency can result from somatic or germline mutations.
- Commercial antibodies for MSH2 and MLH1 offer potential for immunohistochemical detection of MMR deficiency.
Purpose of the Study:
- To evaluate the efficacy of immunohistochemistry (IHC) using MSH2 and MLH1 antibodies for identifying MMR-deficient colorectal cancers.
- To compare IHC staining patterns with microsatellite instability (MSI) status.
Main Methods:
- Immunohistochemical staining for MSH2 and MLH1 expression was performed on formalin-fixed, paraffin-embedded colorectal cancer tissues.
- Staining patterns were analyzed in 23 MSI cancers (including 4 with germline mutations) and 23 microsatellite stable (MSS) cancers.
Main Results:
- All MSS cancers showed positive staining for both MSH2 and MLH1.
- Twenty-two out of 23 MSI cancers displayed absent MMR protein expression (MSH2 or MLH1).
- Immunohistochemistry demonstrated high sensitivity and predictive value for detecting MMR deficiency.
Conclusions:
- Immunohistochemistry is a sensitive and reliable method for detecting MMR deficiency in colorectal cancers.
- This IHC approach can effectively discriminate between MSI and MSS colorectal cancers caused by MSH2 and MLH1 dysfunction.
- IHC is suitable for routine clinical practice to detect MSI and prioritize MMR gene mutational analysis.
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