Tumor progression is characterized by stepwise accumulation of genetic alterations. 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 frequency in metastatic tumors. LOH at 17q21, 13q12-13, 17p13.1 and 11q22-23 was analyzed to determine whether there is a specific involvement of these breast cancer-associated gene loci in the metastatic process. Our data show that distant metastases are characterized by markedly increased LOH frequency at all loci examined. In both gene locus groups, significantly more distant metastases are affected by combined LOH. Furthermore, a significantly reduced postmetastatic survival time has been observed in patients with brain metastases affected by synchronous allelic loss at the four breast cancer-associated gene loci. Our results suggest that cumulative LOH of breast cancer-related gene loci is associated with a more aggressive phenotype of metastatic breast tumors.

Ataxia Telangiectasia Mutated Proteins↗

PubMedDate not supplied

Loss of BRCA2 correlates with reduced long-term survival of sporadic breast cancer patients.

BACKGROUND: The present study was undertaken to analyze the prognostic value of loss of heterozygosity (LOH) at 13q12-13, 17q21 and 17p13, harboring BRCA2, BRCA1 and p53 to predict the clinical course of sporadic breast cancer patients. MATERIALS AND METHODS: LOH analysis was performed by PCR amplification of genomic DNA using nine microsatellite markers. Fifty-three sporadic breast cancer patients were followed clinically for a median of 55 months. Disease-free and overall survival was documented as the endpoint for statistical evaluation. RESULTS: Patients presenting with LOH in their tumor samples at at least one of the loci examined were found to have a reduced overall survival time compared to those retaining heterozygosity (61% versus 48%). Focusing on the three target regions, patients with LOH at the BRCA2 locus died earlier compared to patients retaining heterozygosity (69% versus 50%) and, in addition, BRCA2 LOH-positive patients showed a shorter metastasis-free interval (30 versus 37 months). In a multivariate analysis, LOH at the 13q12-13 locus was found to be a significant predictor for reduced long-term survival (risk ratio 2.33, 95% C.I., 1.0-5.3; p<0.05) and earlier metastases manifestation (risk ratio 2.32, 95% C.I., 1.0-5.3, p<0.05). CONCLUSION: Allelic loss at the BRCA2 locus may be of use as a negative predictor for metastases-free and overall survival.

Adult↗