Loss of heterozygosity accumulation in primary breast carcinomas and additionally in corresponding distant metastases is associated with poor outcome

The occurrence of distant metastases is the most feared manifestation of br east cancer, often occurring years after the primary surgery and associated dth poor survival. The dominant metastatic clone is characterized by an ac cumulation of genetic alterations, but it is not actually known at what sta ge of the metastatic cascade these alterations have occurred, We investigat ed allelic losses during breast cancer progression in a series of 17 primar y breast carcinomas and 22 corresponding brain, liver, lung, and bone metas tases (mean metastasis-free interval, 31 months) by analyzing 19 microsatel lite markers on seven breast cancer- or metastasis-related chromosomal regi ons and correlated the incidence of combined loss of heterozygosity (LOH) w ith metastasis-free and postmetastatic survival, We found that, in comparis on with the corresponding primary tumor, additional LOH events are frequent ly found in metastases and that the incidence of combined LOH in the primar y tumor, plus the occurrence of additional LOH events in the distant metast ases, correlated significantly with decreased postmetastatic survival. Comb ined LOH of the three breast cancer-related chromosomal regions alone or in combination with allelic loss at the p53 gene region seems to have a speci fic influence on the aggressive behavior of metastases, We hypothesize that the occurrence of additional LOH events is either involved in termination of dormancy of micrometastatic tumor cells at distant organ sites or acquir ed during further progression of metastases.