Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Coetzee, SG; Shen, HC; Hazelett, DJ; Lawrenson, K; Kuchenbaecker, K; Tyrer, J; Rhie, SK; Levanon, K; Karst, A; Drapkin, R; Ramus, SJ; Ovarian Cancer Association Consortium, The Consortium of Investigators of Modifiers of BRCA1/2, ; Couch, FJ; Offit, K; Chenevix-Trench, G; Monteiro, ANA; Antoniou, A; Freedman, M; Coetzee, GA; Pharoah, PDP; Noushmehr, H; Gayther, SA; Ovarian Cancer Association Consortium The Consortium of Investigators of Modifiers of BRCA1/2,

Published Date

  • July 2015

Published In

Volume / Issue

  • 24 / 13

Start / End Page

  • 3595 - 3607

PubMed ID

  • 25804953

Electronic International Standard Serial Number (EISSN)

  • 1460-2083

International Standard Serial Number (ISSN)

  • 0964-6906

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddv101

Language

  • eng