RESUMO
BACKGROUND: Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients. METHODS: Forty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools. RESULTS: Genomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients. CONCLUSIONS: These results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Hibridização Genômica Comparativa , Proteína BRCA1/biossíntese , Proteína BRCA2/biossíntese , Neoplasias da Mama/patologia , Análise por Conglomerados , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Mutação , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genéticaRESUMO
OBJECTIVE: To identify molecular biomarkers for endometriosis in peripheral blood lymphocytes by using DNA microarrays. DESIGN: Case-control. SETTING: Multicenter academic research programs. PATIENT(S): Premenopausal women with or without endometriosis, determined by obstetrics and gynecology specialists during surgery. Microarray analysis included six endometriosis patients and five controls; 15 endometriosis patients and 15 controls were analyzed by using real-time reverse-transcription polymerase chain reaction (RT-PCR). Patients with all disease stages were included. INTERVENTION(S): Peripheral blood samples were collected by venipuncture. MAIN OUTCOME MEASURE(S): The expression levels of mRNAs in blood lymphocytes from endometriosis patients and controls were compared with those of a standard total RNA. Gene expression data were validated by real-time RT-PCR analysis. RESULT(S): A gene selection program identified genes that were differentially expressed in samples from endometriosis patients. To validate the gene expression data, the nine most discriminatory genes were analyzed by real-time RT-PCR. Two of the nine genes identified, IL2RG and LOXL1, were shown to be significantly differentially expressed. CONCLUSION(S): This is the first report of genes that are differentially expressed in peripheral blood lymphocytes of patients with endometriosis, which may provide important clues regarding the pathogenesis of this disease. Moreover, they could be considered potential targets for noninvasive diagnostic assays for endometriosis and need to be validated in a larger population.