title: Accumulation of genetic alterations in brain metastases of sporadic breast carcinomas is associated with reduced survival after metastasis.
abstract: 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.
authors.affiliation: Department of General/Thoracic and Vascular Surgery, Medical Faculty of the Technical University of Dresden, Dresden, Germany. monika_hampl@macmailgw.dfci.harvard.edu
authors.forename: M
authors.initials: M
authors.lastname: Hampl
authors.forename: J A
authors.initials: JA
authors.lastname: Hampl
authors.forename: P
authors.initials: P
authors.lastname: Schwarz
authors.forename: S
authors.initials: S
authors.lastname: Frank
authors.forename: M
authors.initials: M
authors.lastname: Hahn
authors.forename: G
authors.initials: G
authors.lastname: Schackert
authors.forename: H D
authors.initials: HD
authors.lastname: Saeger
authors.forename: H K
authors.initials: HK
authors.lastname: Schackert
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D018797:Cell Cycle Proteins; D002877:Chromosomes, Human / Q000235:genetics* / Q000648:ultrastructure; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D015993:Life Tables; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D018895:Microsatellite Repeats; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics; D009378:Neoplasms, Multiple Primary / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017384:Sequence Deletion; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins
chemical_list: D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases