The human mammary-derived growth inhibitor (MDGI) gene: Genomic structure and mutation analysis in human breast tumors

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.