Genetic heterogeneity in ductal carcinoma of the breast

Genetic heterogeneity in breast cancer has been observed both by cytogeneti c and loss of heterozygosity (LOH) analyses; however,the frequency with whi ch genetically heterogeneous clones arise is unknown. In this study, a pane l of 115 breast carcinomas was analyzed to determine the extent of clonal d ivergence in tumor foci at progressive stages of tumor evolution. Intraduct al, infiltrating, and metastatic tumor components were microdissected from each tumor and tested for LOH at 20 microsatellite markers on seven chromos omal arms. Of these cases, 24 (21%) demonstrated genetically divergent clon es during tumor progression. Clonal divergence, inferred from discordant LO H patterns, was observed most commonly between intraductal and infiltrating tumor (18 cases), but was also demonstrated between infiltrating and metas tatic tumor (11 cases). Discordant LOH was observed with markers on one chr omosomal arm in 16 cases, on two in 7 cases, and on four in 1 case, and was observed most commonly with markers on 17p, 17q, and 16q. More detailed mi crodissection of four cases provided evidence for a specific chronology of genetic alterations occurring during the progression of each tumor. The res ults indicate that the different tumor components observed microscopically in breast cancer specimens often represent genetically divergent clones.