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hMLH1 and hMSH2 expression in human hepatocellular carcinoma
L Wang1, A Bani-Hani, D P Montoya
1Department of Laboratory Medicine and Pathology, Mayo Medical School, Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Abstract:
The role of microsatellite instability (MSI) in the pathogenesis of hepatocellular carcinoma (HCC) is incompletely defined. Although high-frequency MSI (MSI-H) is infrequently seen in HCC, some studies have suggested a role for MSI in HCC development. While MSI has been clearly defined for a subset of tumors, in particular colorectal, gastric and endometrial cancers, generally accepted criteria have not been developed for other tumors. Colorectal cancers (CRC) are classified as MSI-H if >30-40% of >5 microsatellite loci analyzed show instability. The MSI-H phenotype is associated with defective DNA mismatch repair (MMR) and is observed in the majority of tumors from patients with hereditary non-polyposis colon cancer (HNPCC) and also in 15% of sporadic CRCs. Inactivating mutations of the hMLH1 or hMSH2 genes lead to defects in MMR in HNPCC. In sporadic CRCs, MMR is usually due to hypermethylation of the hMLH-1 promoter. The role of defective MMR in hepatocellular carcinogenesis is controversial. Immunohistochemistry for hMLH1 and hMSH2 reliably indicates hMLH1 or hMSH2 loss in MSI-H CRC tumors. To investigate the role of defective MMR in HCC carcinogenesis, we performed immunohistochemistry for hMLH1 and hMSH2 on 36 HCCs. BAT26, a microsatellite marker that reliably predicts MSI-H was also examined. All 36 of the tumors stained positively for both hMLH1 and hMSH2, strongly suggesting an absence of either inactivating mutations of hMLH1 and hMSH2 or promoter hypermethylation of hMLH1. None of the tumors showed MSI at the BAT26 locus. These findings suggest that defective MMR does not contribute significantly to hepatocellular carcinogenesis.
Insights
Microsatellite instability (MSI) and DNA mismatch repair (MMR) defects do not appear to play a significant role in hepatocellular carcinoma (HCC) development. This study found no evidence of MSI or MMR deficiency in 36 HCC tumors examined.
Area of Science:
- Hepatobiliary Neoplasms
- Molecular Oncology
- Cancer Pathogenesis
Background:
- The role of microsatellite instability (MSI) in hepatocellular carcinoma (HCC) pathogenesis is not well understood.
- While MSI is a key factor in colorectal, gastric, and endometrial cancers, its significance in HCC remains controversial.
- Defective DNA mismatch repair (MMR) is linked to MSI in other cancers, typically due to gene mutations or promoter hypermethylation.
Purpose of the Study:
- To investigate the potential contribution of defective DNA mismatch repair (MMR) to hepatocellular carcinogenesis.
- To determine the presence of microsatellite instability (MSI) in HCC tumors.
- To assess the expression of MMR proteins hMLH1 and hMSH2 in HCC.
Main Methods:
- Immunohistochemistry was used to evaluate the expression of hMLH1 and hMSH2 proteins in 36 HCC tissue samples.
- The microsatellite marker BAT26, a reliable predictor of high-frequency MSI (MSI-H), was analyzed.
- Tumor samples were assessed for MSI and MMR protein status.
Main Results:
- All 36 HCC tumors examined expressed both hMLH1 and hMSH2 proteins.
- No evidence of microsatellite instability (MSI) was detected at the BAT26 locus in any of the HCC tumors.
- The findings suggest the absence of inactivating mutations or promoter hypermethylation affecting hMLH1/hMSH2.
Conclusions:
- Defective DNA mismatch repair (MMR) does not appear to be a significant factor in the development of hepatocellular carcinoma (HCC).
- Microsatellite instability (MSI) is infrequent and likely not a major driver in HCC pathogenesis.
- Further research may be needed to fully elucidate the molecular mechanisms underlying HCC development.