Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Lawrenson K, Li Q, Kar S, Seo JH, Tyrer J, Spindler TJ, Lee J, Chen Y, Karst A, Drapkin R, Aben KKH, 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, Chenevix-Trench G, Chen A, Chen Z, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Dicks E, Doherty JA, Doerk T, Du Bois A, Duerst M, Eccles D, Easton DT, Edwards RP, Eilber U, Ekici AB, Fasching P, 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 MAT, 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, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LFAG, Matsuo K, Mcguire V, Mclaughlin JR, Nevanlinna H, Mcneish I, Menon U, Modugno F, Moysich KB, Narod SA, Nedergaard L, Ness RB, Azmi MAN, 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, Ramus SJ, 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, 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, Monteiro A, Pharoah PD, Gayther SA, Freedman ML, Grp AOCS, Bowtell D, Webb PM, Defazio A (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 6

Pages Range: 8234

DOI: 10.1038/ncomms9234

Abstract

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P<=10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

Authors with CRIS profile

Involved external institutions

Cedars-Sinai Medical Center United States (USA) (US) Mayo Clinic United States (USA) (US) Beatson West of Scotland Cancer Centre (BWSCC) United Kingdom (GB) University of Pittsburgh United States (USA) (US) University of Sydney (USYD) Australia (AU) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Peter MacCallum Cancer Centre Australia (AU) Dana–Farber Cancer Institute United States (USA) (US) University of Southern California (USC) United States (USA) (US) University of Cambridge United Kingdom (GB) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) University of California Irvine United States (USA) (US) Vanderbilt University United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) University of Texas MD Anderson Cancer Center United States (USA) (US) University of Malaya (UM) / Universiti Malaya Malaysia (MY) University of Hawaii (U.H.) United States (USA) (US) Fred Hutchinson Cancer Research Center Canada (CA) Stanford University United States (USA) (US) Universität Ulm Germany (DE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) University College London (UCL) United Kingdom (GB) University of Glasgow United Kingdom (GB) Helsingin yliopisto / University of Helsinki Finland (FI) Mount Sinai Hospital (MSH) Canada (CA) Kyushu University / 九州大学 Japan (JP) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) University of Copenhagen Denmark (DK) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Texas Southern University (TSU) United States (USA) (US) Memorial Sloan Kettering Cancer Center United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) British Columbia Cancer Agency Canada (CA) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Radboud University Nijmegen Netherlands (NL) Oregon Health and Science University (OSHU) United States (USA) (US) Medical University of South Carolina (MUSC) United States (USA) (US) Danish Cancer Society Research Center Denmark (DK) Duke University United States (USA) (US) Aichi Cancer Center Research Institute Japan (JP) Danish Cancer Society Denmark (DK) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Kliniken Essen-Mitte Germany (DE) Cancer Research Initiatives Foundation (CARIF) / Cancer Research Malaysia (CRM) Malaysia (MY) Cancer Council Victoria Australia (AU) Shanghai Cancer Institute / 上海市肿瘤研究所 China (CN) University of Kansas (KU) United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) University of Southampton United Kingdom (GB) Friedrich-Schiller-Universität Jena Germany (DE) Dartmouth College United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Harvard University United States (USA) (US) University of New Mexico (UNM) / Universidad de Nuevo México United States (USA) (US) Rutgers Cancer Institute of New Jersey United States (USA) (US) N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology Belarus (BY) Xiamen University China (CN) Brigham and Women's Hospital (BWH) United States (USA) (US) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu Poland (PL) The University of Melbourne Australia (AU) Glasgow Royal Infirmary (GRI) United Kingdom (GB) Institut für Humangenetik Wiesbaden Germany (DE) University of Toronto Canada (CA) Yale University United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US)

How to cite

APA:

Lawrenson, K., Li, Q., Kar, S., Seo, J.-H., Tyrer, J., Spindler, T.J.,... Defazio, A. (2015). Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer. Nature Communications, 6, 8234. https://dx.doi.org/10.1038/ncomms9234

MLA:

Lawrenson, Kate, et al. "Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer." Nature Communications 6 (2015): 8234.

BibTeX: Download