Abstract
Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA-like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively). This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies.
Highlights
The triple negative (TN) subtype of breast cancer accounts for 10–17% of all breast carcinomas [1,2,3,4]
The cases where tumours were available were of higher grade (p
Tumours arising in women with hereditary Breast Cancer susceptibility gene 1 (BRCA1) mutations tend to be TN and basal-like, features that are associated with a poor prognosis
Summary
The triple negative (TN) subtype of breast cancer accounts for 10–17% of all breast carcinomas [1,2,3,4]. Triple negative tumours are more likely to be of higher grade, to present with nodal or distant metastases, and there is a relative lack of effective therapies compared to other cancer subtypes, which all contribute to poor disease-free and overall survival [5]. By definition, these tumours are oestrogen receptor (ER) and progesterone receptor (PR) negative and negative for human epidermal growth factor receptor (HER2). Recent comprehensive RNA and DNA profiling analyses have identified at least four distinct subtypes of triple negative breast cancers that may have specific therapeutic targets based on their molecular signatures [8, 9]
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