Abstract
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.
Highlights
The exact timing and contribution of epigenetic reprogramming to carcinogenesis are unclear
We performed epigenome-wide DNA methylation (DNAme) analyses in 215 microscopic foci of normal fallopian tubes from BRCA1/2 mutation carriers (n 1⁄4 56) and controls (n 1⁄4 59) who had their tubes/ovaries removed for riskreduction or other reasons, respectively
The human fallopian tube is one of the very few human organs which allow the study of true preneoplastic reprogramming events because B40% of BRCA mutation carriers are eventually diagnosed with a high-grade serous extra-uterine Mullerian cancers (HGSEMC) originating in the fimbrial end of the fallopian tube, providing an opportunity to examine tissues at elevated cancer risk before morphological evidence of neoplastic transformation
Summary
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 Mullerian cancers (HGSEMC), otherwise referred to as ‘ovarian carcinomas’, which frequently develop from fimbrial cells but not from the proximal portion of the fallopian tube. We compare the DNA methylome of the fimbrial and proximal ends of the fallopian tube in BRCA1/2 mutation carriers and non-carriers. We describe an epigenetic reprogramming phenomenon occurring in the proximal end of the fallopian tube in BRCA mutation carriers, which is not evident in matched controls. We show that this epigenetic reprogramming event is driven by aberrantly high AID (activation-induced cytosine deaminase) expression and is an integral early pre-malignant event in HGSEMC development. Our findings provide the basis for the development of primary ovarian cancer prevention strategies in BRCA1/2 mutation carriers
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