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Women harbouring <jats:italic>BRCA1\/2<\/jats:italic> mutations demonstrate a 30\u201340-fold increased risk of high-grade serous extra-uterine M\u00fcllerian cancers (HGSEMC), otherwise referred to as \u2018ovarian carcinomas\u2019, 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 <jats:italic>BRCA1\/2<\/jats:italic> 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 <jats:italic>BRCA<\/jats:italic> 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 <jats:italic>BRCA1\/2<\/jats:italic> mutation-driven carcinogenesis. Our findings may provide a basis for cancer-preventative strategies.<\/jats:p>","DOI":"10.1038\/ncomms11620","type":"journal-article","created":{"date-parts":[[2016,5,24]],"date-time":"2016-05-24T17:19:57Z","timestamp":1464110397000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution"],"prefix":"10.1038","volume":"7","author":[{"given":"Thomas E.","family":"Bartlett","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kantaraja","family":"Chindera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"McDermott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5294-915X","authenticated-orcid":false,"given":"Charles E.","family":"Breeze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Cooke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Reisel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smita T.","family":"Karegodar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupali","family":"Arora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5290-2151","authenticated-orcid":false,"given":"Stephan","family":"Beck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3708-1732","authenticated-orcid":false,"given":"Usha","family":"Menon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Dubeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Widschwendter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,5,24]]},"reference":[{"key":"BFncomms11620_CR1","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/nature10166","volume":"474","author":"D Bell","year":"2011","unstructured":"Bell, D. et al. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609\u2013615 (2011).","journal-title":"Nature"},{"key":"BFncomms11620_CR2","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.1126\/science.1251827","volume":"343","author":"FJ Couch","year":"2014","unstructured":"Couch, F. J., Nathanson, K. L. & Offit, K. Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science 343, 1466\u20131470 (2014).","journal-title":"Science"},{"key":"BFncomms11620_CR3","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1126\/science.7545954","volume":"266","author":"Y Miki","year":"1994","unstructured":"Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66\u201371 (1994).","journal-title":"Science"},{"key":"BFncomms11620_CR4","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/378789a0","volume":"378","author":"R Wooster","year":"1995","unstructured":"Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789\u2013792 (1995).","journal-title":"Nature"},{"key":"BFncomms11620_CR5","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1126\/science.1251900","volume":"343","author":"MC King","year":"2014","unstructured":"King, M. C. \"The race\" to clone BRCA1. Science 343, 1462\u20131465 (2014).","journal-title":"Science"},{"key":"BFncomms11620_CR6","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1158\/1055-9965.EPI-11-0775","volume":"21","author":"N Mavaddat","year":"2012","unstructured":"Mavaddat, N. et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1\/2 (CIMBA). Cancer Epidemiol. Biomarkers Prev. 21, 134\u2013147 (2012).","journal-title":"Cancer Epidemiol. 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A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations. Gynecol. Oncol. 109, 168\u2013173 (2008).","journal-title":"Gynecol. Oncol."},{"key":"BFncomms11620_CR10","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/j.ccr.2013.10.013","volume":"24","author":"R Perets","year":"2013","unstructured":"Perets, R. et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models. Cancer Cell 24, 751\u2013765 (2013).","journal-title":"Cancer Cell"},{"key":"BFncomms11620_CR11","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1126\/science.1230184","volume":"339","author":"ML Suva","year":"2013","unstructured":"Suva, M. L., Riggi, N. & Bernstein, B. E. Epigenetic reprogramming in cancer. 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