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Altered expression of hMLH1 and hMSH2 protein in endometrial carcinomas with microsatellite instability
A Staebler1, S F Lax, L H Ellenson
1Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Abstract:
Microsatellite instability (MI) has been observed in approximately 20% of presumably sporadic cases of uterine endometrioid carcinoma (UEC). A previous mutational analysis of the 4 known DNA mismatch repair genes (hMSH2, hMLHI, hPMS1, and hPMS2) on a small number of Ml-positive tumors detected mutations in only 2 of 8 cases, both in hMSH2. To further explore the underlying cause of MI in UEC, we analyzed the protein expression of hMSH2 and hMLHI in UEC of known MI status. Formalin-fixed, paraffin-embedded archival tissue from 21 UECs was analyzed by immunoperoxidase staining with monodonal antibodies against hMLH1 and hMSH2 protein. Tumors were evaluated for presence of nuclear staining by 3 investigators. Lack of nuclear hMLHI staining was found in 7 of 13 carcinomas with MI, but in none of 8 carcinomas without MI (Fischer's exact, 0.018). Lack of nuclear hMSH2 staining was found in 3 of the MI-positive cases, but none of the MI-negative cases (not statistically significant). Taken together, lack of nuclear staining of either hMLH1 or hMSH2 was found in 9 of 13 cases with MI and in none of 8 cases without MI (Fischer's exact, 0.005). We conclude that MI in sporadic UEC appears to be associated with lack of expression of either hMLH1 or hMSH2, suggesting that inactivation of these genes may be responsible for MI in most MI-positive sporadic UECs.
Insights
Microsatellite instability (MI) in uterine endometrioid carcinoma (UEC) is often linked to the loss of DNA mismatch repair proteins. This study found that lack of hMLH1 or hMSH2 protein expression is associated with MI in most UEC cases.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Microsatellite instability (MI) is present in about 20% of sporadic uterine endometrioid carcinoma (UEC).
- Previous studies showed limited mutations in DNA mismatch repair (MMR) genes (hMSH2, hMLHI, hPMS1, hPMS2) in MI-positive UEC.
- The exact cause of MI in UEC requires further investigation.
Purpose of the Study:
- To investigate the protein expression of hMSH2 and hMLHI in UEC.
- To determine the association between MMR protein expression and microsatellite instability status in UEC.
Main Methods:
- Immunohistochemical analysis of hMSH2 and hMLHI protein expression using formalin-fixed, paraffin-embedded UEC tissues.
- Evaluation of nuclear staining in 21 UEC samples with known MI status.
- Statistical analysis using Fischer's exact test to assess significance.
Main Results:
- Loss of nuclear hMLH1 staining was observed in 7 of 13 MI-positive UECs, but not in MI-negative cases (p=0.018).
- Loss of nuclear hMSH2 staining was found in 3 MI-positive cases, but none of the MI-negative cases (not significant).
- Combined loss of hMLH1 or hMSH2 nuclear staining occurred in 9 of 13 MI-positive UECs versus none of the MI-negative cases (p=0.005).
Conclusions:
- Microsatellite instability in sporadic UEC is strongly associated with the lack of hMLH1 or hMSH2 protein expression.
- Inactivation of hMLH1 or hMSH2 likely underlies microsatellite instability in the majority of MI-positive sporadic UECs.
- MMR protein deficiency is a key factor in the pathogenesis of UEC with microsatellite instability.