Microsatellite instability in ductal carcinoma in situ of the breast.

Microsatellite instability (MI+) is associated with defects in mismatch repair, resulting in a 'mutator' phenotype and the development and progression of cancer. MI+ has been documented in invasive breast carcinomas. This study was undertaken to determine whether MI+ is found in the early non-invasive form of breast cancer, ductal carcinoma in situ (DCIS). We examined microdissected ducts from 23 cases of DCIS with 11 markers comprising mono-, di-, and trinucleotide repeats from six chromosomal regions. Five tumours (22 per cent) displayed MI+ at two or more loci, in all ducts examined. A further seven (30 per cent) tumours showed alterations at a single locus (the DM-1 trinucleotide), and for two of these, heterogeneity between ducts was observed. Alterations at microsatellite repeat motifs in the coding regions of four cancer-associated genes (TGF beta RII, IGFIIR, BAX, and E2F-4) were not observed. Immunohistochemistry revealed that there was no loss of reactivity for the mismatch repair proteins, MLH1, MSH2, and PMS2, in the DCIS cases. In general, MI+ tumours and those with alterations at the DM-1 microsatellite were predominantly of higher nuclear grade and expressing c-erbB-2, suggesting that aberrations in DNA repair functions may lead to the acquisition of a more aggressive phenotype in breast cancer.