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Frequent loss of expression without sequence mutations of the DCC gene in primary gastric cancer
1Departments of Pathology, Surgery, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
Abstract:
Loss of heterozygosity (LOH) on chromosome 18q21 is frequently found in various human cancers, suggesting the presence of tumour suppressor gene(s) in this chromosomal region. DCC is the most likely target of LOH because loss or reduction of DCC expression has been found in many types of cancers. However, few reports have focused on sequence mutations of this gene. We investigated sequence mutations and expression of DCC in primary gastric cancers. We studied mutations in 25 of the 29 DCC exons by PCR-SSCP in 17 primary gastric cancers exhibiting LOH on 18q21. No mutations of DCC were found in any of the tumours, although 78% (47/60) of the primary tumours showed apparent loss or reduction of DCC expression by immunohistochemistry. Analysis of methylation status of DCC revealed that methylation frequently occurred in both primary tumours (75%; 45/60) and corresponding non-cancerous gastric mucosae (72%; 43/60). Methylated status of DCC was significantly correlated with the loss of DCC expression in primary tumours (P< 0.01). These results indicate that DCC is frequently silenced, probably by epigenetic mechanisms instead of sequence mutations in gastric cancer.
Insights
Gastric cancers frequently lose DCC gene expression, not due to mutations, but epigenetic silencing via methylation. This finding is crucial for understanding gastric cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Loss of heterozygosity (LOH) on chromosome 18q21 is common in human cancers.
- The DCC gene is a suspected tumor suppressor frequently downregulated in various cancers.
- Previous research has primarily focused on LOH, with limited investigation into DCC sequence mutations.
Purpose of the Study:
- To investigate sequence mutations and expression of the DCC gene in primary gastric cancers.
- To determine the role of DCC gene alterations in gastric tumorigenesis.
- To explore the mechanisms behind DCC gene silencing in gastric cancer.
Main Methods:
- Studied mutations in 25 of 29 DCC exons using PCR-SSCP in 17 primary gastric cancers with 18q21 LOH.
- Assessed DCC expression levels via immunohistochemistry in 60 primary gastric tumors.
- Analyzed DCC gene methylation status in both primary tumors and adjacent non-cancerous gastric mucosa.
Main Results:
- No DCC sequence mutations were detected in the analyzed gastric tumors.
- A significant majority (78%) of primary gastric tumors exhibited loss or reduction of DCC expression.
- DCC gene methylation was prevalent in both tumors (75%) and non-cancerous mucosa (72%) and strongly correlated with reduced DCC expression (P<0.01).
Conclusions:
- DCC gene silencing in gastric cancer is primarily driven by epigenetic mechanisms, specifically methylation, rather than sequence mutations.
- The findings suggest that epigenetic silencing of DCC contributes to gastric tumorigenesis.
- Further research into epigenetic regulation of tumor suppressor genes like DCC is warranted for gastric cancer therapy.
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