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Purpose: Genetic alterations were previously identified in normal epithelia adjacent to invasive cancers. The aim of this study was to determine DNA methylation in histologically normal tissues from multiple geographic zones adjacent to primary breast tumors., Experimental Design: First, methylation status of a 4-kb region of RASSF1A promoter was interrogated using oligonucleotide-based microarray in 144 samples (primary tumors, 47; adjacent normals, 69; reduction mammoplasty tissues, 28). Second, allelic imbalance (AI)/loss of heterozygosity (LOH) surrounding RASSF1A promoter were analyzed in 30 samples (tumors, 8; adjacent normals, 22). Third, global methylation screening of 49 samples (tumors, 12; adjacent normals, 25; reduction mammoplasty, 12) was done by differential methylation hybridization. Real-time quantitative methylation-specific PCR was used to validate the microarray findings., Results: DNA methylation in the core RASSF1A promoter was low in reduction mammoplasty tissues (P=0.0001) when compared with primary tumors. The adjacent normals had an intermediate level of methylation. The regions surrounding the core were highly methylated in all sample types. Microsatellite markers showed AI/LOH in tumors and some of the adjacent normals. Concurrent AI/LOH and DNA methylation in RASSF1A promoter occurred in two of six tumors. Global methylation screening uncovered genes more methylated in adjacent normals than in reduction mammoplasty tissues. The methylation status of four genes was confirmed by quantitative methylation-specific PCR., Conclusions: Our findings suggest a field of methylation changes extending as far as 4 cm from primary tumors. These frequent alterations may explain why normal tissues are at risk for local recurrence and are useful in disease prognostication.

The mammographic features of carcinoma originating within a fibroadenoma in 24 patients were studied by means of retrospective review of pathologic slides. Histologic examination showed that the lesions were lobular carcinoma in situ (LCIS) (seven patients), ductal carcinoma in situ (DCIS) (13 patients), synchronous LCIS and invasive lobular carcinoma (one patient), and synchronous LCIS and DCIS (three patients). In all patients the mammographic manifestation was a mass 1.0 cm or greater in diameter; 14 masses were 1-2 cm in diameter, and the remainder were more than 2 cm in diameter. Features that were considered suspect included large size, indistinct margins, and clustered microcalcifications. In three patients, microcalcifications within the mass raised suspicion of malignancy. At histologic examination these microcalcifications were associated with the intraductal carcinoma harbored in the fibroadenoma in only one of these patients. Fibroadenomas that harbor carcinoma may be indistinguishable from common benign fibroadenomas, but their occurrence is rare. In this study, a single patient had invasive lobular carcinoma; all the other lesions were in situ lesions.