The risk of local recurrence in the breast following lumpectomy without radiotherapy is ∼40%. Despite its normal histological appearance, the residual breast must harbor pre-malignant disease. Genetic alterations were previously identified in the normal epithelia immediately adjacent to invasive cancers. We sought to evaluate multiple zones (1-4 cm away from tumor sites) of histologically normal breast tissue for epigenetic alterations, knowing that these changes can lead to repression of tumor suppressor genes and promote tumorigenesis. Using methylation microarray approaches, we identified a number of key genes, including RASSF1A, CYP26A1, KCNAB1, and SNCA, frequently hypermethylated in normal breast tissues adjacent to cancer. Subsequent independent studies confirm that 70% of the cases showed concurrent hypermethylation of these loci in tumors and adjacent normal tissues. This and the detailed mapping of the 4-kb RASSF1A promoter for a total of 144 samples (primary tumors, 49; adjacent normal tissues, 69; breast reduction mammoplasty tissues, 26) suggest the presence of a large field of methylation changes which can be as far as 4 cm away from primary tumor sites. In a few cases, altered methylation occurs in the contralateral normal breast. These frequent alterations may offer a molecular explanation for why apparently normal breast tissues are at increased risk for cancer and provide a quantitative means for predicting future local recurrence.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]