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Genomic organization and mutation analyses of the DR5/TRAIL receptor 2 gene in colorectal carcinomas
1Department of First Surgery, Tokyo Medical and Dental University School of Medicine, Japan.
Abstract:
The DR5/TRAIL receptor 2 gene is a novel TNF receptor family member and induces apoptosis by overexpression of its product. DR5 is located on chromosome 8p21, where allelic deletions are often observed in advanced colorectal cancers. This evidence led us to examine whether or not mutations of the DR5 gene exist in these tumors. We determined the genomic structure of DR5, which consists of nine exons. DR5 has two alternatively spliced isoforms. All seven colorectal cancer (CRC) cell lines examined expressed the longer isoform predominantly. No somatic mutation was found in 41 CRC cases. Loss of heterozygosity of DR5 was found in nine (52.9%) of the 17 informative cases, which is similar to the previously reported frequencies observed for 8p21-22 in colorectal cancers. These findings suggest that inactivation of the DR5 gene may play only a small role, if any, in colorectal tumorigenesis.
Insights
The Death Receptor 5 (DR5) gene, crucial for apoptosis, showed no somatic mutations in colorectal cancers. Loss of heterozygosity was observed, suggesting a minor role for DR5 gene inactivation in tumor development.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- The DR5/TRAIL receptor 2 gene is a novel member of the TNF receptor family.
- Overexpression of DR5 induces apoptosis.
- The DR5 gene is located on chromosome 8p21, a region frequently deleted in advanced colorectal cancers.
Purpose of the Study:
- To investigate the presence of DR5 gene mutations in colorectal tumors.
- To assess the role of DR5 gene alterations in colorectal tumorigenesis.
Main Methods:
- Determined the genomic structure of the DR5 gene (nine exons).
- Analyzed DR5 expression in seven colorectal cancer cell lines.
- Screened 41 colorectal cancer cases for somatic mutations in the DR5 gene.
- Assessed loss of heterozygosity at the DR5 locus in 17 informative colorectal cancer cases.
Main Results:
- DR5 has two alternatively spliced isoforms, with the longer isoform predominantly expressed in colorectal cancer cell lines.
- No somatic mutations were detected in the DR5 gene in 41 colorectal cancer cases.
- Loss of heterozygosity of DR5 was observed in 52.9% of informative cases, consistent with frequencies at 8p21-22.
Conclusions:
- The findings suggest that somatic mutations in the DR5 gene are not a common event in colorectal tumorigenesis.
- Loss of heterozygosity at the DR5 locus occurs frequently, but its role in colorectal cancer development appears limited.
- Inactivation of the DR5 gene likely plays a minimal role, if any, in the development of colorectal cancers.