Determination of Molecular Profiles of BRCA1 and BRCA2 Breast Cancers.

Background BRCA1 and BRCA2 genes are known to be the target of germline mutations in familial breast cancers, which represent 5% of the total breast cancer population. Mutation screening of these genes is performed in suspected familial breast cancer cases but a causative mutation is found in only 30% of patients. Therefore the development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1 - or BRCA2 - mutated breast cancers.Material and MethodsArray-CGH and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the bases of at least 3 affected first degree relatives or at least 2 affected first degree relatives with breast cancer at an average age of 45 years. Tumoral DNA was co-hybridized with pooled normal blooded DNA from 21 individuals on a 4407 BAC-array (CIT-V8) provided by the CIT program and manufactured by Integragen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Clinical, pathological and genomic data were retrieved through Annotator, the CIT cancer database and the analysis was performed by using the R statistical software along with the CIT R packages.ResultsUsing supervised clustering analyses we identified 2 transcriptomic signatures, one for BRCA1 -mutated breast cancers consisting of 600 probes sets and another for BRCA2 -mutated breast cancers also consisting of 600 probes sets. We also defined CGH-array signatures, based on a presence of specific genomic rearrangements, one for BRCA1 -mutated breast cancers and one for BRCA2 -mutated breast cancers.ConclusionThis study has identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. Moreover, we identified specific genomic rearrangements in these breast cancers which could be screened for in a diagnostic setting using FISH thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6132.