Accumulation of genetic alterations in brain metastases of sporadic breastcarcinomas is associated with reduced survival after metastasis

Tumor progression is characterized by stepwise accumulation of genetic alte rations. To identify alterations associated with breast cancer metastasis, an analysis of comparative loss of heterozygosity (LOH) was performed on 38 primary sporadic breast carcinomas and 16 distant metastases. Two loci at 5q21 and 18q21 were chosen because of their reported increased deletion fre quency in metastatic tumors. LOH at 17q21, 13q12-13, 17p13.1 and 11q22-23 w as analyzed to determine whether there is a specific involvement of these b reast cancer-associated gene loci in the metastatic process. Our data show that distant metastases are characterized by markedly increased LOH frequen cy at all loci examined. In both gene locus groups, significantly more dist ant metastases are affected by combined LOH. Furthermore, a significantly r educed postmetastatic survival time has been observed in patients with brai n metastases affected by synchronous allelic loss at the four breast cancer -associated gene loci. Our results suggest that cumulative LOH of breast ca ncer-related gene loci is associated with a more aggressive phenotype of me tastatic breast tumors.