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

Journal article


Publication Details

Author(s): 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
Journal: Nature Communications
Publication year: 2015
Volume: 6
Pages range: 8234
ISSN: 2041-1723


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.


FAU Authors / FAU Editors

Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
Fasching, Peter PD Dr.
Professur für Translationale Frauenheilkunde und Geburtshilfe
Hein, Alexander PD Dr.
Frauenklinik


External institutions with authors

Aichi Cancer Center Research Institute
Beatson West of Scotland Cancer Centre (BWSCC)
Brigham and Women's Hospital (BWH)
British Columbia Cancer Agency
Cancer Council Victoria
Cancer Research Initiatives Foundation (CARIF)
Cedars-Sinai Medical Center
Dana–Farber Cancer Institute
Danish Cancer Society
Danish Cancer Society Research Center
Dartmouth College
Deutsches Krebsforschungszentrum (DKFZ)
Duke University
Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB)
Fred Hutchinson Cancer Research Center
Friedrich-Schiller-Universität Jena
Glasgow Royal Infirmary (GRI)
Harvard University
Haukeland University Hospital / Haukeland universitetssykehus
Helsingin yliopisto / University of Helsinki
H. Lee Moffitt Cancer Center & Research Institute
Institut für Humangenetik Wiesbaden
Kliniken Essen-Mitte
Kyushu University / 九州大学
Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie
Mayo Clinic
Medical University of South Carolina (MUSC)
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Memorial Sloan Kettering Cancer Center
Mount Sinai Hospital (MSH)
National Cancer Institute (NCI)
N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology
Oregon Health and Science University (OSHU)
Peter MacCallum Cancer Centre
Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU)
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Radboud University Nijmegen
Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC)
Roswell Park Cancer Institute
Rutgers Cancer Institute of New Jersey
Shanghai Cancer Institute / 上海市肿瘤研究所
Stanford University
Texas Southern University (TSU)
The University of Melbourne
Universität Ulm
University College London (UCL)
University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven
University of California Irvine
University of Cambridge
University of Copenhagen
University of Glasgow
University of Hawaii (U.H.)
University of Kansas (KU)
University of Malaya (UM) / Universiti Malaya
University of New Mexico
University of Pittsburgh
University of Southampton
University of Southern California (USC)
University of Sydney
University of Texas Health Science Center at Houston (UTHealth)
University of Texas MD Anderson Cancer Center
University of Toronto
Vanderbilt University
Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu
Xiamen University


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: 

Last updated on 2019-21-07 at 08:00