Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution

Thomas E. Bartlett, Kantaraja Chindera, Jacqueline McDermott, Charles E. Breeze, William R. Cooke, Allison Jones, Daniel Reisel, Smita T. Karegodar, Rupali Arora, Stephan Beck, Usha Menon, Louis Dubeau and Martin Widschwendter ()
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Thomas E. Bartlett: UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London
Kantaraja Chindera: UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London
Jacqueline McDermott: UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London
Charles E. Breeze: UCL Cancer Institute, University College London
William R. Cooke: UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London
Allison Jones: UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London
Daniel Reisel: UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London
Smita T. Karegodar: UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London
Rupali Arora: UCL Cancer Institute, University College London
Stephan Beck: UCL Cancer Institute, University College London
Usha Menon: UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London
Louis Dubeau: USC/Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California
Martin Widschwendter: UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11620

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