title: Determination of molecular markers for BRCA1 and BRCA2 heterozygosity using gene expression profiling.
abstract: Approximately 5% of all breast cancers can be attributed to an inherited mutation in one of two cancer susceptibility genes, BRCA1 and BRCA2. We searched for genes that have the potential to distinguish healthy BRCA1 and BRCA2 mutation carriers from noncarriers based on differences in expression profiling. Using expression microarrays, we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control noncarriers. We identified 137 probe sets in BRCA1 carriers and 1,345 in BRCA2 carriers with differential gene expression. Gene Ontology analysis revealed that most of these genes relate to regulation pathways of DNA repair processes, cell-cycle regulation, and apoptosis. Real-time PCR was conducted on the 36 genes, which were most prominently differentially expressed in the microarray assay; 21 genes were shown to be significantly differentially expressed in BRCA1 and/or BRCA2 mutation carriers as compared with controls (P < 0.05). On the basis of a validation study with 40 mutation carriers and 17 noncarriers, a multiplex model that included six or more coincidental genes of 18 selected genes was constructed to predict the risk of carrying a mutation. The results using this model showed sensitivity 95% and specificity 88%. In summary, our study provides insight into the biologic effect of heterozygous mutations in BRCA1 and BRCA2 genes in response to ionizing irradiation-induced DNA damage. We also suggest a set of 18 genes that can serve as a prediction and screening tool for BRCA1 or BRCA2 mutational carriers by using easily obtained lymphocytes.
authors: Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. asalmon@hadassah.org.il
authors: Asher Y
authors: AY
authors: Salmon
authors: Mali
authors: M
authors: Salmon-Divon
authors: Tamar
authors: T
authors: Zahavi
authors: Yulia
authors: Y
authors: Barash
authors: Rachel S
authors: RS
authors: Levy-Drummer
authors: Jasmine
authors: J
authors: Jacob-Hirsch
authors: Tamar
authors: T
authors: Peretz
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006580:Genetic Carrier Screening / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor