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[The relationship between frameshift mutations of transforming growth factor-beta type II receptor, insulin growth
Guo-ting Chen1, Zheng-gang Zhu, Hao-ran Yin
1Department of Surgery, Tongji University Affiliated Oriental Hospital, Shanghai 200120, China. guotingchen@163.com
Objective:
To determine the microsatellite instability in gastric carcinomas, examine the frameshift mutations of transforming growth factor-beta type II receptor (TGFbetaRII), insulin growth factor II receptor (IGFIIR), bcl-2 associated X protein (BAX) and E2F4, and investigate whether or how alterations of the TGFbetaRII, IGFIIR, BAX and E2F4 gene are associated with MSI in gastric cancer.
Methods:
Formalin-fixed, paraffin-embedded gastrectomy specimens and matching normal tissues of 65 cases of gastric carcinomas were retrieved from shanghai Ruijin Hospital and Shanghai East Hospital. DNA was extracted from tissue sections using phenol chloral isoamyl alcohol. Sections with no more than 50% of tumor cell areas were isolated by microdissection. DNA was amplified by PCR-based single strand conformation polymorphism (SSCP) for microsatellite analysis and was sequenced directly. Frameshift mutations in the coding regions, repetitive mononucleotide tracts of (A)10 for TGFbetaRII, (G)8 for IGFIIR, (G)8 for BAX, and trinucleotide repeats of (AGC)13 for transcription factors E2F4 were detected using PCR. Tumors were classified as being microsatellite stable (MSS) or having a low frequency of MSI (MSI-L, one of markers different in the tumor) or a high frequency of MSI (MSI-H, two or more of markers different).
Results:
Eleven cases (18.0%) showed MSI-L, 12 (19.7%) showed MSI-H and 38 (62.3%) cases showed MSS. The mutation rates of TGFbetaRII, IGFIIR, BAX and E2F4 gene were 19.7%, 4.9%, 6.6% and 16.4% respectively. Among the 12 MSI-H gastric cancers, there were 10 TGFbetaRII mutations, 3 IGFIIR mutations, 4 BAX mutations and 10 E2F4 gene mutations. The alterations in the repeats of the related genes presented polymorphisms. Associations of MSI-H status and mutations of the 4 genes were highly significant (P < 0.01, respectively). No repeat tracts mutations in TGFbetaRII, IGFIIR, BAX and E2F4 gene were found in MSS tumors.
Conclusions:
The repeat coding regions within TGFbetaRII, IGFIIR, BAX and E2F4 gene are the targets of microsatellite instability. Frameshift mutations of the 4 genes play an important role in the development and progression of gastric cancers with microsatellite instability.
Insights
Microsatellite instability (MSI) is linked to frameshift mutations in TGFbetaRII, IGFIIR, BAX, and E2F4 genes in gastric cancer. These mutations are crucial for the development and progression of MSI-high gastric tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastric cancer is a significant global health concern.
- Microsatellite instability (MSI) is a known molecular feature in various cancers, including gastric cancer.
- Specific gene mutations are implicated in the pathogenesis of gastric cancer.
Purpose of the Study:
- To determine the frequency of microsatellite instability (MSI) in gastric carcinomas.
- To examine frameshift mutations in transforming growth factor-beta type II receptor (TGFbetaRII), insulin growth factor II receptor (IGFIIR), bcl-2 associated X protein (BAX), and E2F4.
- To investigate the association between alterations in these genes and MSI in gastric cancer.
Main Methods:
- Analysis of 65 gastric carcinoma specimens using DNA extraction and microdissection.
- Microsatellite analysis via PCR-based single-strand conformation polymorphism (SSCP) and direct sequencing.
- Detection of frameshift mutations in TGFbetaRII, IGFIIR, BAX, and E2F4 genes using PCR.
Main Results:
- 18.0% of cases showed low MSI (MSI-L), 19.7% showed high MSI (MSI-H), and 62.3% were microsatellite stable (MSS).
- Mutation rates were 19.7% for TGFbetaRII, 4.9% for IGFIIR, 6.6% for BAX, and 16.4% for E2F4.
- MSI-H tumors exhibited a highly significant association with mutations in all four genes (P < 0.01), with no mutations found in MSS tumors.
Conclusions:
- Repeat coding regions in TGFbetaRII, IGFIIR, BAX, and E2F4 genes are targets of microsatellite instability.
- Frameshift mutations in these four genes play a significant role in the development and progression of microsatellite instability-high gastric cancers.
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