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Hum Mol Genet. 2015 Jul 1;24(13):3595-607. doi: 10.1093/hmg/ddv101. Epub 2015 Mar 24.

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

Collaborators (146)

Tyrer J, Anton-Culver H, Antonenkova N, Baker H, Bandera EV, Bean Y, Beckmann MW, Berchuck A, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Butzow R, Campbell IG, Carty K, Chang-Claude J, Chen A, Chen Z, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Dicks E, Doherty JA, Dörk T, Bois Ad, Dürst M, Eccles D, Easton DF, Edwards RP, Eilber U, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Goode EL, Goodman MT, Grownwald J, Harrington P, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MA, Hillemanns P, Hogdall E, Hogdall C, Hosono S, Iversen ES, Jakubowska A, James P, Jensen A, Ji BT, Karlan BY, Kjaer SK, Kelemen LE, Kellar M, Kelley JL, Kiemeney LA, Krakstad C, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, McNeish I, Menon U, Modugno F, Moysich KB, Narod SA, Nedergaard L, Ness RB, Azmi MA, Odunsi K, Olson SH, Orlow I, Orsulic S, Weber RP, Pearce CL, Pejovic T, Pelttari LM, Permuth-Wey J, Phelan CM, Pike MC, Poole EM, Risch HA, Rosen B, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schildkraut JM, Schwaab I, Sellers TA, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Sucheston L, Tangen IL, Teo SH, Terry KL, Thompson PJ, Timorek A, Tsai YY, Tworoger SS, Tyrer J, van Altena AM, Van Nieuwenhuysen E, Vergote I, Vierkant RA, Wang-Gohrke S, Walsh C, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Woo YL, Wu X, Wu AH, Yang H, Zheng W, Ziogas A.

Author information

1
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.
2
Department of Preventive Medicine, Keck School of Medicine and.
3
Department of Preventive Medicine, Keck School of Medicine and, Department of Urology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
4
Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
5
Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel.
6
Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA.
7
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
8
Clinical Genetics Service, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
9
Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
10
Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
11
Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA and.
12
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.
13
Department of Preventive Medicine, Keck School of Medicine and, simon.gayther@med.usc.edu.

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.

PMID:
25804953
PMCID:
PMC4459387
DOI:
10.1093/hmg/ddv101
[Indexed for MEDLINE]
Free PMC Article

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