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The exact timing and contribution of epigenetic reprogramming to carcinogenesis are unclear. Women harbouring BRCA1/2 mutations demonstrate a 30-40-fold increased risk of high-grade serous extra-uterine Müllerian cancers (HGSEMC), otherwise referred to as 'ovarian carcinomas', which frequently develop from fimbrial cells but not from the proximal portion of the fallopian tube. Here we compare the DNA methylome of the fimbrial and proximal ends of the fallopian tube in BRCA1/2 mutation carriers and non-carriers. We show that the number of CpGs displaying significant differences in methylation levels between fimbrial and proximal fallopian tube segments are threefold higher in BRCA mutation carriers than in controls, correlating with overexpression of activation-induced deaminase in their fimbrial epithelium. The differentially methylated CpGs accurately discriminate HGSEMCs from non-serous subtypes. Epigenetic reprogramming is an early pre-malignant event integral to BRCA1/2 mutation-driven carcinogenesis. Our findings may provide a basis for cancer-preventative strategies.

Original publication

DOI

10.1038/ncomms11620

Type

Journal article

Journal

Nat Commun

Publication Date

24/05/2016

Volume

7

Keywords

Adolescent, Adult, Aged, Aged, 80 and over, BRCA1 Protein, BRCA2 Protein, Carcinogenesis, Cell Line, Tumor, CpG Islands, Cytidine Deaminase, DNA Methylation, Epigenesis, Genetic, Epithelial Cells, Epithelium, Fallopian Tubes, Female, Humans, Middle Aged, Mutation, Ovarian Neoplasms, Ovariectomy, Primary Cell Culture, Retrospective Studies, Time Factors, Young Adult