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Somatic alterations of the SMAD-2 gene in human colorectal cancers
Y Takagi1, H Koumura, M Futamura
1Department of Surgery II, Gifu University School of Medicine, Japan.
Abstract:
The SMAD-2 gene, which is located at 18q21, has been identified as a candidate tumour-suppressor gene from work on colorectal cancers. The aim of the present study was to determine the clinical alterations and the significance of its mutations in a series of colorectal cancers previously examined for SMAD-4/DPC-4 gene. Mutation analyses of the SMAD-2 gene were carried out on cDNA samples from 36 primary colorectal cancer specimens using a combination of the polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and DNA sequencing. Only one missense mutation (2.8%), producing an amino acid substitution in the highly conserved region, and two homozygous deletions (5.5%) of the total coding region of the SMAD-2 gene were detected in the 36 cancers. The SMAD-2 gene may play a role as a candidate tumour-suppressor gene in a small fraction of colorectal cancers. However, allelic loss at 18q21 is very often seen in this type of tumour. Even in combination with changes in SMAD-4, the observed frequency was not sufficient to account for all 18q21 deletions in colorectal cancers. Thus, another tumour-suppressor gene, such as DCC, discovered as the first tumour-suppressor candidate in the region may also exist in this chromosome region.
Insights
Mutations in the SMAD-2 gene are infrequent in colorectal cancers, suggesting it acts as a tumor suppressor in a small subset. Further research is needed to identify other tumor suppressor genes on chromosome 18q21.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The SMAD-2 gene at 18q21 is a potential tumor suppressor in colorectal cancer.
- Previous studies have implicated SMAD-4/DPC-4 in colorectal tumorigenesis.
- Allelic loss at 18q21 is common in colorectal tumors.
Purpose of the Study:
- To investigate the frequency and clinical significance of SMAD-2 gene mutations in colorectal cancer.
- To assess the role of SMAD-2 in conjunction with SMAD-4 alterations in colorectal cancer development.
Main Methods:
- Mutation analysis of the SMAD-2 gene in 36 colorectal cancer specimens.
- Utilized polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), and DNA sequencing.
- Examined cDNA samples for missense mutations and homozygous deletions.
Main Results:
- Identified one missense mutation (2.8%) and two homozygous deletions (5.5%) in the SMAD-2 gene.
- These alterations were found in a small fraction of the analyzed colorectal cancers.
- The combined alterations of SMAD-2 and SMAD-4 did not fully explain the observed 18q21 deletions.
Conclusions:
- SMAD-2 gene mutations play a role in a limited number of colorectal cancers.
- The high frequency of 18q21 allelic loss suggests the involvement of additional tumor suppressor genes, such as DCC.
- Further investigation is warranted to identify other critical tumor suppressor genes in this chromosomal region.