Molecular genetic studies of early breast cancer evolution.

In the past few years there has been an explosion in the number of patients diagnosed with hyperplastic breast disease and in situ breast cancer. Based on epidemiological data, these morphologically defined lesions 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 "initiated" (e.g. atypical ductal hyperplasia [ADH]), and early "transformed" lesions which are malignant but not yet invasive (e.g. ductal carcinoma in situ [DCIS]). They may represent sequential evolutionary stages in the ontogeny of invasive breast cancer, with each morphologically defined stage resulting from accumulating genetic changes culminating in a transformed clonal lineage capable of invasion and metastasis. Using loss-of-heterozygosity (LOH) analysis, we are studying the genetic 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 same breast, strongly supporting a precursor/product relationship between these lesion and the cancers they accompany.