Our data indicated that p53, BRCA1, ATM, PIK3CA, and HER2 alterations specifically correlate with clinicopathological characteristics of Bulgarian patients with breast cancer. Of these genes, only mutated p53 showed significant, though not independent, negative effect on overall survival.

Promoter hypermethylation was shown to be involved in human cancerogenesis through silencing gene expression. Several studies were dedicated to explore the frequency and clinical significance of BRCA1 hypermethylation in sporadic breast cancer to identify a specific molecular and clinico-pathological phenotype. However the available data are limited and rather too heterogeneous. In this study we investigated the level of methylation in the promoter region of BRCA1 and its correlation with clinico-pathological and molecular characteristics in a group of 135 Bulgarian patients. Methylation specific PCR was applied to determine methylation status of tumor samples. Clinical impact of BRCA1 hypermethylation was estimated using standard statistical methods including Fisher's exact and the Chi-squared tests, the Kaplan-Meier method, the univariate and multivariate Cox proportional hazards regression model. We found that hypermethylation was present in 17.04% of the cases (23/135). Patients with hypermethylation in BRCA1 displayed favorable clinical status as their tumors were smaller in size (P = 0.066), lacked p53 gene mutations (P = 0.073) and were of lobular type (P = 0.046). The presence of hypermethylation was weakly associated with better overall survival (P = 0.2) with a hazard ratio of 0.47 (95% CI 0.14-1.54, P = 0.213). Our study provides the first data on the BRCA1 hypermethylation of Bulgarian patients and contributes to elucidation of its clinical significance in sporadic breast cancer. Key words: Breast cancer, BRCA1, Hypermethylation, Clinicopathological characteristics, Overall survivalBreast cancer (BC) represents a major challenge to modern human oncology because of its high and constantly increasing frequency, and growing mortality and morbidity rate in women below the age of 45. Every year in Bulgaria, approximately 3600 women are diagnosed and about 1300 die of BC (1). The major risk factors are sex, age, family predisposition, as well as some reproductive and hormonal factors like early menarche and late menopause, late first childbirth, shorter breastfeeding period, use of oral contraceptives and hormone replacement therapy. Clinically BC is very heterogeneous, which is due to heterogeneity in disease mechanisms.BC results from accumulation of genetic and epigenetic changes in tumor suppressor genes and proto-oncogenes. Some of these genes -р53, PIK3CA, CHEK2, АТМ, HER2, are involved in the pathogenesis of different type of tumors. Others are specific only to breast/ovarian cancer -BRCA1 and BRCA2. A large number of studies demonstrate a correlation between the genetic/epigenetic status of BC related genes and clinicopathological characteristics of the patients. Such investigations could contribute to a more effective BC prevention and therapy, which will increase the survival rate and will significantly improve the quality of life of the patients. However, the results so far are contradictory and need further elucidation.BRCA1 (BReast CAncer susceptibility gene 1) tumor suppressor gene maps to 17...