Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Kar SP, Tyrer JP, Li Q, Lawrenson K, Aben KKH, Anton-Culver H, Antonenkova N, Chenevix-Trench G, Baker H, Bandera EV, Bean YT, Beckmann M, Berchuck A, Bisogna M, Bjorge L, Bogdanova N, Brinton L, Brooks-Wilson A, Butzow R, Campbell I, Carty K, Chang-Claude J, Chen YA, Chen Z, Cook LS, Cramer D, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Dicks E, Doherty JA, Doerk T, Du Bois A, Duerst M, Eccles D, Easton DF, Edwards RP, 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, Hein A, Heitz F, Hildebrandt MAT, Hillemanns P, Hogdall E, Hogdall CK, Hosono S, Iversen ES, Jakubowska A, Paul J, Jensen A, Ji BT, Karlan BY, Kjaer SK, Kelemen LE, Kellar M, Kelley J, 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 L, Matsuo K, Mcguire V, Mclaughlin JR, Mcneish IA, Menon U, Modugno F, Moysich KB, Narod SA, Nedergaard L, Ness RB, Nevanlinna H, 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, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Sucheston-Campbell LE, 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 A, Yang H, Zheng W, Ziogas A, Sellers TA, Monteiro ANA, Freedman ML, Gayther SA, Pharoah PDP (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 24

Pages Range: 1574-84

Journal Issue: 10

DOI: 10.1158/1055-9965.EPI-14-1270

Abstract

Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574-84. ©2015 AACR.

Authors with CRIS profile

Involved external institutions

Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Radboud University Nijmegen Netherlands (NL) University of Pittsburgh United States (USA) (US) Oregon Health and Science University (OSHU) United States (USA) (US) University of Cambridge United Kingdom (GB) University of Southern California (USC) United States (USA) (US) Dana–Farber Cancer Institute United States (USA) (US) University of South Florida (USF) 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 United States (USA) (US) Stanford University United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) Universität Ulm Germany (DE) Mayo Clinic United States (USA) (US) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Harvard University United States (USA) (US) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu Poland (PL) Duke University United States (USA) (US) Memorial Sloan Kettering Cancer Center United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) Helsingin yliopisto / University of Helsinki Finland (FI) University of Copenhagen Denmark (DK) Women's College Hospital Canada (CA) University College London (UCL) United Kingdom (GB) University of Glasgow United Kingdom (GB) Mount Sinai Hospital (MSH) Canada (CA) Kyushu University / 九州大学 Japan (JP) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Texas Southern University (TSU) United States (USA) (US) British Columbia Cancer Agency Canada (CA) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Medical University of South Carolina (MUSC) United States (USA) (US) Danish Cancer Society Denmark (DK) Beatson West of Scotland Cancer Centre (BWSCC) United Kingdom (GB) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Kliniken Essen-Mitte Germany (DE) 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) Princess Anne Hospital United Kingdom (GB) Friedrich-Schiller-Universität Jena Germany (DE) Dartmouth College United States (USA) (US) University of New Mexico (UNM) / Universidad de Nuevo México United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Peter MacCallum Cancer Centre Australia (AU) Rutgers Cancer Institute of New Jersey United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology Belarus (BY) Ramsay Sime Darby Health Care (RSDHC) Malaysia (MY) 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) Aichi Cancer Center Research Institute Japan (JP)

How to cite

APA:

Kar, S.P., Tyrer, J.P., Li, Q., Lawrenson, K., Aben, K.K.H., Anton-Culver, H.,... Pharoah, P.D.P. (2015). Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk. Cancer Epidemiology Biomarkers & Prevention, 24(10), 1574-84. https://doi.org/10.1158/1055-9965.EPI-14-1270

MLA:

Kar, Siddhartha P., et al. "Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk." Cancer Epidemiology Biomarkers & Prevention 24.10 (2015): 1574-84.

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