Immunohistochemical staining of hMLH1 and hMSH2 reflects microsatellite instability status in ovarian carcinoma

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
Modern Pathology (Impact Factor: 6.19). 12/2006; 19(11):1414-20. DOI: 10.1038/modpathol.3800672
Source: PubMed
Microsatellite instability is due to defects in the family of DNA repair genes, primarily hMLH1 and hMSH2, which can be detected by immunohistochemical staining. However, it is unclear whether immunohistochemical staining can accurately predict microsatellite instability status. We sought here to evaluate the sensitivity, specificity, and predictive values of immunostaining for the expression of the DNA mismatch-repair genes hMLH1 or hMSH2 in predicting microsatellite instability in ovarian carcinoma. Tissue microarrays with specimens from 322 women with primary ovarian carcinoma were stained with antibodies to hMLH1 and hMSH2; cases in which either hMLH1 or hMSH2 were negative were analyzed for microsatellite instability with the five-marker panel recommended by the National Cancer Institute (BAT26, BAT25, D5S346, D2S123, and D17S250). Microsatellite instability was also analyzed in another 19 cases selected at random in which both hMLH1 and hMSH2 were positive. Tumors with instability at two or more of the five NCI markers were considered to have a high level of microsatellite instability; tumors showing instability at only one marker were considered microsatellite instability-low; and tumors in which no markers exhibited microsatellite instability were considered microsatellite stable. We found that negative staining for hMLH1 protein (five cases) or hMSH2 protein (two cases) was associated with high level of microsatellite instability. The sensitivity and specificity of immunohistochemical staining for hMLH1 were 62 and 100% and those of hMSH2 alone were 25 and 100%. Combining loss of expression of both hMLH1 and hMSH2 led to sensitivity, specificity, and positive and negative predictive values of 87, 100, 100, and 95%. These results suggest that use of a two-molecule panel (hMLH1 and hMSH2) can accurately determine the microsatellite instability status of patients with ovarian cancer.

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    • "The level of MSI was classified as high (MSI-H) when two or more markers tested demonstrated instability, low (MSI-L) when one of the markers tested demonstrated instability and stable (MSS) when no instability was detected . LOH was defined as an identical pattern in one of the two alleles, but complete loss in the second allele and was scored for all the markers [42]. Repeatability was confirmed by randomly rerunning 20 samples and verifying the results obtained. "
    [Show abstract] [Hide abstract] ABSTRACT: The role of defective mismatch repair (MMR) system in ovarian carcinoma is not well defined. The purpose of the study was to determine the relationship between microsatellite instability (MSI), promoter methylation and protein expression of MMR genes in epithelial ovarian carcinoma (EOC). MSI and promoter methylation of MLH1, MSH2 and PMS2 genes were studied using PCR methods in the study cohort. A small subset of samples was used to analyze the protein expression by immunohistochemistry (IHC). MSI was observed in > 60% of tumor samples and 47% of normal ovaries. MLH1 was methylated in 37.5% and 64.3% EOCs and LMP tumors. The loss of immunoexpression of MMR genes was not seen in ovarian tumors. There was no correlation between MSI, promoter methylation and protein expression of the MMR genes suggesting that each may function independently. MSI is a common event in ovarian carcinoma and may increase the clinical awareness of the subset of tumors.
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    • "This group found that 4/6 ovarian clear cell carcinomas with MSI-H demonstrated loss of MLH1 or MSH2 protein expression with immunohistochemical staining; whereas, none of the 3 clear cell carcinomas with MSI-L and only 2/33 of the MSS clear cell carcinomas demonstrated loss of MLH1 or MSH2 protein expression (Cai et al., 2004). On the other hand, loss of MLH1 and MSH2 protein expression is highly predictive of MSI-H in unselected sporadic ovarian carcinoma (Rosen et al., 2006). Malander et al. (2006) tested 128 ovarian carcinomas from patients at the Lund University Hospital for MSI using the mononucleotide markers BAT25, BAT26, BAT40, BAT34C4 and the dinucleotide markers D2S123 and D5S346 in immunohistochemical testing for expression of MSH2, MLH1, MSH6 and PMS2 proteins. "
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    [Show abstract] [Hide abstract] ABSTRACT: Background : The aim of this study was to clarity the incidence and role of microsatellite instability (MSI) in sporadic ovarian epithelial cancers (OEC). We investigated the MSI status and mismatch repair (MMR) protein expression in OEC. Methods: MSI was examined by fluorescence-based polymerase chain reaction using five NCl panel markers (BAT25, BAT26, D2S123, D5S346 and D17S250) in 46 cases of OEC. Immunohistochemistry (IHC) for hMLH1 and hMSH2 was performed. Results: Seven cases (15.2%) exhibited high-frequency MSI (MSI-H), one exhibited low-frequency MSI (MSI-L), and the remaining 38 demonstrated microsatellite stability (MSS). MSI-H in OEC was not associated with histologic grade, FIGO stage, tumor size, mitoses or histologic type. Loss of expression of either hMLH1 or hMSH2 was observed in 4 of the 7 (59.3%) MSI-H cases, whereas 4 of the 39 (10.3%) MSI-L or MSS tumors revealed loss of expression of MMR proteins. The sensitivity and specificity of immunohistochemistry for hMLH1 and hMSH2 were 57.1% and 89.7%. Conclusions: Our data suggest that a genetic defect in the MMR system might play a role in the carcinogenesis of a minor subset of sporadic OEC however, immunohistochemical testing for hMLH1 and hMSH2 cannot accurately determine microsatellite instability status in OEC.
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