Abstract
Objective:The purpose of our study was to determine the frequency of BRCA1 promoter hypermethylation and its association with expression changes of BRCA1 and main morphological features in sporadic breast cancer. Methods:A retrospective review of cases was performed to select those with specific morphological features suggestive of breast cancer. BRCA1 promoter hypermethylation and changes in protein expression were evaluated in 30 cancerous and 30 non-cancerous tissue samples. A tissue microarray containing samples from normal and tumor tissue was prepared and stained for BRCA1 protein expression using a commercially available monoclonal antibody against BRCA1 (Ab-1) clone MS110 (mAb). DNA was extracted using modified protocol of Qiagen minikit. DNA was modified using a Bisulfite conversion kit and BRCA1 hypermethylation was detected using a methylation specific PCR. Results:Promoter hypermethylation was negative in 30 non-cancerous samples with retained BRCA1 protein expression. Methylation was positive in 82.6% (n=19/23) of the sporadic cancer samples that had loss of BRCA1 expression and 50% (n=2/4) of the samples with equivocal protein expression. Methylation was negative in all the sporadic breast cancer samples (n=3/3) with retained protein expression. Chi-square analysis showed significant association of BRCA1 promoter methylation with decreased protein expression (P=0.016) and co-existence of loss of BRCA1 and Her2neu at chromosome 17 (P=0.026) respectively. There was no significant association of BRCA1 methylation with morphological features excluding necrosis (P=0.035). Promoter hypermethylation was found to be most common (68.75%) among Triple Negative Breast Cancer (TNBC) females less than 45 years old. Conclusion:Our study suggests that BRCA1 promoter hypermethylation has significant contribution in sporadic breast carcinogenesis. This was our preliminary study in Pakistan. Further studies aimed to determine the in-depth mechanisms of BRCA1 epigenetics in TNBC. BRCAness enriched phenotype in TNBC might be used as a biomarker for the exploitation of therapeutic and clinical implications.
Highlights
Breast cancer is a complex disorder, which involves the interplay of various genes and pathways
Our study suggests that BRCA1 promoter hypermethylation has significant contribution in sporadic breast carcinogenesis
Promoter hypermethylation was negative in non-cancerous breast tissue samples with retained BRCA1 protein expression
Summary
Breast cancer is a complex disorder, which involves the interplay of various genes and pathways. Pakistan has the highest prevalence of breast cancer in Asia excluding. Israel as one in every eight women is suffering from breast cancer. The annual Age Standardized Incidence Rate for breast cancer stood at: 43.3/100,000 females at a global level and 450.3/100,000 females in Pakistan (Badar et al, 2015). The frequency of breast cancer has increased by more than 20%, and mortality rate has increased by 14% in Pakistan since past few years (Jemal et al, 2011). Breast cancer occurs in hereditary, familial and sporadic forms.
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