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The human mammary-derived growth inhibitor (MDGI) gene: genomic structure and mutation analysis in human breast
C M Phelan1, C Larsson, S Baird
1Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
Abstract:
The mammary-derived growth inhibitor (MDGI) gene is a candidate tumor suppressor gene for human breast cancer. It has been shown to reduce the tumorigenicity of breast cancer cell lines in nude mice, and loss of expression of this gene has been shown in primary breast tumors. Furthermore, the human MDGI gene has been mapped to human chromosome 1p32-p35, a common region of deletion in sporadic breast tumors. We have determined the genomic structure of the human MDGI gene from a cosmid clone mapping to chromosome 1p32-p35 and have more finely mapped the MDGI gene relative to chromosome 1p microsatellite markers. The gene covers approximately 8 kb of genomic DNA and is divided into four exons. In an attempt to identify possible inactivating mutations in the MDGI gene in human breast cancer, we have sequenced all four exons and their surrounding splice junctions in 30 sporadic breast tumors. Ten of these tumors showed loss of heterozygosity (LOH) in the 1p32-p35 region, with 5 tumors showing LOH in the subregion containing the MDGI gene. No mutations were found in this analysis. A polymorphism was identified in exon 2 in the constitutional DNA of 1/30 cases in this study, which resulted in the conversion of a lysine to an arginine residue at codon 53. This variant was present in the constitutional DNA of a further 3/26 women with sporadic breast cancer and 2/90 control individuals (P = 0.20). Despite experimental evidence that MDGI has tumor suppressor activity, our data suggest that mutations in the coding region are uncommon in human breast tumorigenesis.
Insights
The mammary-derived growth inhibitor (MDGI) gene, a potential breast cancer suppressor, was investigated for mutations. Analysis of 30 tumors revealed no coding mutations, suggesting MDGI is rarely inactivated in human breast cancer.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The mammary-derived growth inhibitor (MDGI) gene is a candidate tumor suppressor for human breast cancer.
- Loss of MDGI expression and deletions in its chromosomal region (1p32-p35) are observed in breast tumors.
- MDGI has demonstrated tumor suppressor activity in experimental models.
Purpose of the Study:
- To determine the genomic structure of the human MDGI gene.
- To finely map the MDGI gene's location on chromosome 1p.
- To identify inactivating mutations in the MDGI gene's coding regions in sporadic breast tumors.
Main Methods:
- Determined the genomic structure of the MDGI gene from a cosmid clone.
- Fine-mapped the MDGI gene using chromosome 1p microsatellite markers.
- Sequenced all four exons and splice junctions of the MDGI gene in 30 sporadic breast tumors.
Main Results:
- The MDGI gene spans approximately 8 kb and consists of four exons.
- Loss of heterozygosity (LOH) in the 1p32-p35 region was observed in 10 tumors, with 5 showing LOH in the MDGI subregion.
- No inactivating mutations were detected in the sequenced exons and splice junctions.
- A polymorphism in exon 2, resulting in a lysine to arginine substitution at codon 53, was identified but not significantly associated with breast cancer risk.
Conclusions:
- Mutations in the coding region of the MDGI gene are uncommon in human breast tumorigenesis.
- Despite experimental evidence of tumor suppressor activity, MDGI's coding sequence does not appear to be a frequent target for inactivation in sporadic breast cancers.