title: Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution.
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.
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London WC1E 6AU, UK.|Department of Statistical Science, University College London, London WC1E 7HB, UK.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Bartlett
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London WC1E 6AU, UK.
authors.forename: Kantaraja
authors.initials: K
authors.lastname: Chindera
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London WC1E 6AU, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: McDermott
authors.affiliation: Department of Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Charles E
authors.identifier: 0000-0002-5294-915X
authors.initials: CE
authors.lastname: Breeze
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London WC1E 6AU, UK.
authors.forename: William R
authors.initials: WR
authors.lastname: Cooke
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London WC1E 6AU, UK.
authors.forename: Allison
authors.initials: A
authors.lastname: Jones
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London WC1E 6AU, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Reisel
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London WC1E 6AU, UK.
authors.forename: Smita T
authors.initials: ST
authors.lastname: Karegodar
authors.affiliation: Department of Pathology, UCL Cancer Institute, University College London, London WC1E 6BT UK.
authors.forename: Rupali
authors.initials: R
authors.lastname: Arora
authors.affiliation: Department of Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Stephan
authors.identifier: 0000-0001-5290-2151
authors.initials: S
authors.lastname: Beck
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London WC1E 6AU, UK.
authors.forename: Usha
authors.identifier: 0000-0003-3708-1732
authors.initials: U
authors.lastname: Menon
authors.affiliation: Department of Pathology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London WC1E 6AU, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D003564:Cytidine Deaminase / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D005187:Fallopian Tubes / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010052:Ovariectomy; D061251:Primary Cell Culture; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase