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