Genotype and phenotype in hereditary and sporadic breast cancers

Abstract

10538 Background: BRCA1 protein is involved in distinct DNA-repair processes. Germline mutations in BRCA1 gene confer cancer susceptibility. A frequent mechanism for epigenetic inactivation is hypermethylation of the CpG island in promoters of tumours suppressor genes. BRCA1 promoter hypermethylation has been found in a variable percentage of breast cancers (15–30%). BRCA1-associated breast cancers are usually high-grade, poorly differentiated and stain negative for HER2/neu, oestrogen and progesterone receptors (ER, PgR). Many studies have shown that hereditary BRCA1 and basal-like sporadic breast tumours have a similar phenotype and gene expression signature. Methods: By clinical criteria, 223 patients were selected and, for each patient, the probability to carry a BRCA1 mutation was calculated using the software BRCAPRO and Manchester Score System. All patients were studied by direct sequencing and MLPA of BRCA1 Open Reading Frames (ORFs). Thirty sporadic breast carcinomas, from women undergone surgery for primary invasive breast carcinoma between 1995 and 2001, were selected on the basis of negative staining for ER, PgR and HER2/neu (“BRCA-like”). In these patients, Methylation Specific-PCR and Bisulfite Sequencing on genomic DNA (obtained from sections of paraffin-embedded tissues and modified with sodium bisulfite) were used to assess the methylation pattern of BRCA1 promoter. BRCA1 immunohystochemical analysis (IHC) was performed in all patients. Results: We identified 17 patients with deleterious germline mutations in BRCA1. In “BRCA-like” patients, 13 methylated and 17 unmethylated cases were found by methylation analysis of BRCA1 promoter. The BRCA1 IHC was performed in all available samples ( table 1 ). Conclusions: Hypermethylation of BRCA1 promoter was found in 43% of “BRCA- like” patients. Expression of BRCA1 seems to correlate with hypermethylation of its promoter. Further studies are in progress to better understand the possible role of BRCA1 promoter hypermethylation in sporadic breast cancers. [Table: see text] No significant financial relationships to disclose.