Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci.
作者信息
Coetzee Simon G, Shen Howard C, Hazelett Dennis J, Lawrenson Kate, Kuchenbaecker Karoline, Tyrer Jonathan, Rhie Suhn K, Levanon Keren, Karst Alison, Drapkin Ronny, Ramus Susan J, Couch Fergus J, Offit Kenneth, Chenevix-Trench Georgia, Monteiro Alvaro N A, Antoniou Antonis, Freedman Matthew, Coetzee Gerhard A, Pharoah Paul D P, Noushmehr Houtan, Gayther Simon A
机构信息
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.
Department of Preventive Medicine, Keck School of Medicine and.
出版信息
Hum Mol Genet. 2015 Jul 1;24(13):3595-607. doi: 10.1093/hmg/ddv101. Epub 2015 Mar 24.
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.