title: Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci.
abstract: Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.
authors: Department of Genetics - Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Monte Alegre, Ribeirão Preto-SP CEP: 14049-900, Brazil, Center for Cell Based Therapy, Rua Tenente Catão Roxo, 2501, Monte Alegre, Ribeirão Preto, SP, CEP: 14051-140, Brazil.
authors: Simon G
authors: SG
authors: Coetzee
authors: Department of Preventive Medicine, Keck School of Medicine and.
authors: Howard C
authors: HC
authors: Shen
authors: Department of Preventive Medicine, Keck School of Medicine and, Department of Urology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors: Dennis J
authors: DJ
authors: Hazelett
authors: Department of Preventive Medicine, Keck School of Medicine and.
authors: Kate
authors: K
authors: Lawrenson
authors: Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors: Karoline
authors: K
authors: Kuchenbaecker
authors: Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors: Jonathan
authors: J
authors: Tyrer
authors: Department of Preventive Medicine, Keck School of Medicine and, Department of Urology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors: Suhn K
authors: SK
authors: Rhie
authors: Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel.
authors: Keren
authors: K
authors: Levanon
authors: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA.
authors: Alison
authors: A
authors: Karst
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Ronny
authors: R
authors: Drapkin
authors: Department of Preventive Medicine, Keck School of Medicine and.
authors: Susan J
authors: SJ
authors: Ramus
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Fergus J
authors: FJ
authors: Couch
authors: Clinical Genetics Service, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: Kenneth
authors: K
authors: Offit
authors: Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
authors: Georgia
authors: G
authors: Chenevix-Trench
authors: Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors: Alvaro N A
authors: AN
authors: Monteiro
authors: Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors: Antonis
authors: A
authors: Antoniou
authors: Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA and.
authors: Matthew
authors: M
authors: Freedman
authors: Department of Preventive Medicine, Keck School of Medicine and, Department of Urology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors: Gerhard A
authors: GA
authors: Coetzee
authors: Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors: Paul D P
authors: PD
authors: Pharoah
authors: Department of Genetics - Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Monte Alegre, Ribeirão Preto-SP CEP: 14049-900, Brazil, Center for Cell Based Therapy, Rua Tenente Catão Roxo, 2501, Monte Alegre, Ribeirão Preto, SP, CEP: 14051-140, Brazil, Center for Integrative Systems Biology - CISBi, NAP/USP, Rua Catão Roxo, 2501, Monte Alegre, Ribeirão Preto, SP CEP: 14051-140, Brazil.
authors: Houtan
authors: H
authors: Noushmehr
authors: Department of Preventive Medicine, Keck School of Medicine and, simon.gayther@med.usc.edu.
authors: Simon A
authors: SA
authors: Gayther
mesh_terms: D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D002843:Chromatin; D006657:Histones