The role of MAD2 gene in chromosomal instability in colorectal cancers

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Several genes were known to be involved in chromosomal instability in cancer. Among them, MAD2 gene plays an important role in binding of spindle fibers to the centromeric region of each chromosome. To date, no mutations were found in MAD2 gene. Recently, lower expression of MAD2 was reported to be related with chromosomal instability. Therefore, chromosomal instability will be caused by haploinsufficiency, in which the protein level is halved and is much lower than needed. We have searched for the mutation of MAD2 gene in the gastrointestinal cancers, but found no mutations. We then performed a luciferase reporter assay using the promoter of MAD2 gene containing novel single nucleotide polymorphism (SNP). The results indicated that this SNP did not affect the MAD2 promoter activity at all. Since promoter hypermethylation is an epigenetic mechanism for silencing the gene, we developed the methylation specific PCR assay for MAD2 promoter. MAD2 promoter was found to be methylated even in peripheral blood mononuclear cells from healthy subjects. Accordingly, it is important to determine which CpG dinucleotides in the promoter are methylated and to correlate the promoter activity with the site of methylation. Moreover, the MAD2 protein level detected by immunostaining were found to be a marker for hepatic metastasis in gastric cancers.