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Updated: Jun 20, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H)
Makiko Kawaguchi1, Kouji Banno, Megumi Yanokura
1Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Abstract:
Microsatellite instability (MSI) is an indicator of DNA instability and is caused by abnormalities in DNA mismatch repair (MMR) genes such as hMLH1, hMSH2 and hMSH6. MSI occurs frequently in endometrial cancer (in approximately 30% of cases), and accumulation of gene mutations due to MSI may therefore have a major role in the mechanism of malignant transformation. However, a responsible target gene has not been identified in endometrial cancer. In this study, we analyzed mutations in 11 cancer-related genes with mononucleotide repeats susceptible to MSI in a coding region [hMSH3 (A8), hMSH6 (C8), TGF-beta RII (A10), MBD4 (A10), BAX (G8), PTEN (A6 in exon 7), HDAC2 (A9), EPHB2 (A9), Caspase-5 (A10), TCF-4 (A9) and Axin2 (G7)] in 22 patients with MSI-H sporadic endometrial cancer. Mutations in hMSH6 (C8) and TGF-beta RII (A10) were found most frequently, at rates of 36.3% (8/22) each. Mutations of BAX (G8) and TCF-4 (A9), which are common in MSI-positive colorectal cancer, occurred at rates of 22.7 and 0%, respectively, which suggests that the MSI target gene may differ between endometrial and colorectal cancers. Mutations in hMSH6 (C8) were correlated with reduced protein expression (p=0.042) and patients with these mutations had significantly more mutations in mononucleotide repeats in other cancer-related genes compared to patients without hMSH6 (C8) mutations (p=0.042). This suggests the possibility of a novel cascade in carcinogenesis of endometrial cancer in which MSI mutates hMSH6 (C8), increases gene instability, and leads to accumulation of mutations in other cancer-related genes. To our knowledge, this is the first report to show that hMSH6 (C8) has an important role as an MSI target gene in sporadic endometrial cancer.
Insights
Microsatellite instability (MSI) in endometrial cancer frequently involves mutations in the hMSH6 gene. This suggests hMSH6 plays a key role in cancer development by increasing overall gene instability.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Microsatellite instability (MSI) indicates DNA instability due to DNA mismatch repair (MMR) gene defects.
- MSI is common in endometrial cancer (approx. 30%), potentially driving malignant transformation through accumulated mutations.
- The specific target genes responsible for MSI in endometrial cancer remain unidentified.
Purpose of the Study:
- To identify MSI target genes in sporadic endometrial cancer.
- To investigate the role of specific genes with MSI-susceptible mononucleotide repeats in endometrial carcinogenesis.
Main Methods:
- Analysis of mutations in 11 cancer-related genes with MSI-susceptible mononucleotide repeats in 22 MSI-H sporadic endometrial cancer patients.
- Assessed mutations in genes including hMSH3, hMSH6, TGF-beta RII, MBD4, BAX, PTEN, HDAC2, EPHB2, Caspase-5, TCF-4, and Axin2.
- Correlated hMSH6 mutations with protein expression and the frequency of mutations in other MSI target genes.
Main Results:
- Mutations in hMSH6 (36.3%) and TGF-beta RII (36.3%) were the most frequent.
- BAX mutations occurred at 22.7%, while TCF-4 mutations were absent, suggesting differences between endometrial and colorectal cancer MSI targets.
- hMSH6 mutations correlated with reduced protein expression and a higher mutation burden in other cancer-related genes.
Conclusions:
- hMSH6 (C8) is identified as a significant MSI target gene in sporadic endometrial cancer.
- A potential novel carcinogenic cascade involves MSI-induced hMSH6 mutations, leading to increased genomic instability and subsequent mutations in other cancer-related genes.
- These findings highlight hMSH6's critical role in endometrial cancer pathogenesis.
