Alterations in protooncogenes and tumor-suppressor genes at the DNA and/or protein level, which indicate the biological properties of individual breast cancers, led us to design a study encompassing the dilemma of "epigenetic silencing-driven genomic instabilities." In this study, we analyzed the promoter methylation of potent mismatch repair genes (hmlh1 and hmsh2) for the first time in 232 Indian patients with primary breast cancer (using methylation-specific polymerase chain reaction and expressional analysis). The study evaluates the gamut of epigenetic aberrations as well as genomic instabilities (microsatellite instabilities and loss of heterozygosity) and includes analysis of BAT-25, BAT-26, D2S123, D5S346, and D17S250. We observed hypermethylation of the hmlh1 gene in 43.5% of patients with primary breast cancer, of whom 66.9% had locally advanced breast cancer (stage IIIA, IIIB, and IIIC) (P < .0001). Similarly, we also found hypermethylation of the hmsh 2 gene in 16% of primary breast cancer cases. Of these patients, 21.3% had locally advanced breast cancer (P = . 01). To determine the effect of methylation, we also performed expressional studies using reverse transcriptase polymerase chain reaction and Northern blotting, but we were unable to get any significant expression in the presence of hypermethylation of either gene (hmlh1 and hmsh2). Interestingly, statistical analysis revealed that hypermethylation of the hmlh1 gene is one of the peculiar attributes of locally advanced breast cancer. In addition, this study indicates that for more sensitive stage-specific diagnosis or prognosis, both methylation of promoter and expression studies must be considered in the analyses in a reproducible manner. Therefore, pinpointing the methylation fingerprints (5'CpG island methylation) of potent DNA repairing genes not only shows the specific attributes of locally advanced breast cancer but also provides important insight into the mode of therapy to be used by clinical oncologists.