title: Levels of DNA Methylation Vary at CpG Sites across the BRCA1 Promoter, and Differ According to Triple Negative and "BRCA-Like" Status, in Both Blood and Tumour DNA.
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.
authors.affiliation: Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Sarah L
authors.identifier: http://orcid.org/0000-0001-9452-3344
authors.initials: SL
authors.lastname: Daniels
authors.affiliation: Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: George J
authors.initials: GJ
authors.lastname: Burghel
authors.affiliation: Leeds Institute of Cancer and Pathology, Section of Pathology and Tumour Biology, Wellcome Trust Brenner Building, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Chambers
authors.affiliation: Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, S10 2TH, United Kingdom.
authors.forename: Shadi
authors.initials: S
authors.lastname: Al-Baba
authors.affiliation: Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Connley
authors.affiliation: Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Brock
authors.affiliation: Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Cramp
authors.affiliation: Department of Histopathology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, S10 2JF, United Kingdom.
authors.forename: Olena
authors.initials: O
authors.lastname: Dotsenko
authors.affiliation: Academic Unit of Pathology, Department of Neuroscience, Faculty of Medicine, Dentistry & Health, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Octavia
authors.initials: O
authors.lastname: Wilks
authors.affiliation: Academic Unit of Surgical Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Lynda
authors.initials: L
authors.lastname: Wyld
authors.affiliation: Academic Unit of Pathology, Department of Neuroscience, Faculty of Medicine, Dentistry & Health, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.affiliation: Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.|Sheffield Institute for Nucleic Acids (SInFoNiA), University of Sheffield, Western Bank, Sheffield, S10 2TN, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D064726:Triple Negative Breast Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm