MOLECULAR-GENETIC STUDIES OF EARLY BREAST-CANCER EVOLUTION

In the past few years there has been an explosion in the number of pat ients diagnosed with hyperplastic breast disease and in situ breast ca ncer. Based on epidemiological data, these morphologically defined les ions may be categorized as those with little malignant potential (e.g. typical hyperplasia or proliferative disease without atypia [PDWA]), those with significant malignant potential which may already be ''init iated'' (e.g. atypical ductal hyperplasia [ADH]), and early ''transfor med'' lesions which are malignant but not yet invasive (e.g. ductal ca rcinoma in situ [DCIS]). They may represent sequential evolutionary st ages in the ontogeny of invasive breast cancer, with each morphologica lly defined stage resulting from accumulating genetic changes culminat ing in a transformed clonal lineage capable of invasion and metastasis . Using loss-of-heterozygosity (LOH) analysis, we are studying the gen etic changes associated with these lesions in archival tissue samples. 50% (6/12) of the proliferative lesions (PDWA and ADH) and 80% of the DCIS shared their LOH patterns with more advanced lesions from the sa me breast, strongly supporting a precursor/product relationship betwee n these lesions and the cancers they accompany.