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

Coetzee SG, Shen HC, Hazelett DJ, Lawrenson K, Kuchenbaecker K, Tyrer J, Rhie SK, Levanon K, Karst A, Drapkin R, Ramus SJ, Couch FJ, Offit K, Chenevix-Trench G, Monteiro ANA, Antoniou A, Freedman M, Coetzee GA, Pharoah PDP, Noushmehr H, Gayther SA, Hein A, Ziogas A (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Human Molecular Genetics Oxford University Press (OUP): Policy B - Oxford Open Option B

Book Volume: 24

Pages Range: 3595-3607

Journal Issue: 13

DOI: 10.1093/hmg/ddv101

Abstract

Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most singlenucleotide 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 nongynecological 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 with CRIS profile

Alexander Hein Department of Obstetrics and Gynaecology

Involved external institutions

University of Southern California (USC) US United States (USA) (US) University of São Paulo / Universidade de São Paulo (USP) BR Brazil (BR) Memorial Sloan Kettering Cancer Center US United States (USA) (US) Mayo Clinic US United States (USA) (US) H. Lee Moffitt Cancer Center & Research Institute US United States (USA) (US) Dana–Farber Cancer Institute US United States (USA) (US) University of Cambridge GB United Kingdom (GB) Chaim Sheba Medical Center at Tel HaShomer / המרכז הרפואי עש חיים שיבא – תל השומר‎‎ IL Israel (IL) University of California Irvine US United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU)

How to cite

APA:

Coetzee, S.G., Shen, H.C., Hazelett, D.J., Lawrenson, K., Kuchenbaecker, K., Tyrer, J.,... Ziogas, A. (2015). Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci. Human Molecular Genetics, 24(13), 3595-3607. https://doi.org/10.1093/hmg/ddv101

MLA:

Coetzee, Simon G., et al. "Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci." Human Molecular Genetics 24.13 (2015): 3595-3607.

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