Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk

Siddhartha P. Kar, Jonathan P. Tyrer, Qiyuan Li, Kate Lawrenson, Katja K.H. Aben, Hoda Anton-Culver, Natalia Antonenkova, Georgia Chenevix-Trench, Helen Baker, Elisa V. Bandera, Yukie Tarumi Bean, Matthias W. Beckmann, Andrew Berchuck, Maria Bisogna, Line Bjørge, Natalia Bogdanova, Louise Brinton, Angela Brooks-Wilson, Ralf Butzow, Ian CampbellKaren Carty, Jenny Chang-Claude, Yian Ann Chen, Zhihua Chen, Linda S. Cook, Daniel Cramer, Julie M. Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Joe Dennis, Ed Dicks, Jennifer Anne Doherty, Thilo Dörk, Andreas Du Bois, Matthias Dürst, Diana M Eccles, Douglas F Easton, Robert P. Edwards, Arif B Ekici, Peter A. Fasching, Brooke L. Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind M Glasspool, Ellen L Goode, Marc T Goodman, Jacek Grownwald, Patricia Harrington, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Estrid Hogdall, Claus K. Hogdall, Satoyo Hosono, Edwin S. Iversen, Anna Jakubowska, James Paul, Allan Jensen, Bu-tian Ji, Beth Y. Karlan, Susanne Krüger Kjaer, Linda E. Kelemen, Melissa Kellar, Joseph Kelley, Lambertus A. Kiemeney, Camilla Krakstad, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon M. Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain A McNeish, Usha N Menon, Francesmary Modugno, Kirsten B Moysich, Steven A Narod, Lotte Nedergaard, Roberta B Ness, Heli Nevanlinna, Kunleodunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, Celeste Leigh Pearce, Tanja Pejovic, Liisa M Pelttari, Jennifer Permuth-Wey, Catherine M Phelan, Malcolm C Pike, Elizabeth M Poole, Susan J Ramus, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga Birgitte Salvesen, Joellen M Schildkraut, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Lara E. Sucheston-Campbell, Ingvild L Tangen, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Agnieszka Timorek, Ya-Yu Tsai, Shelley S Tworoger, Anne Mvan Altena, Els Van Nieuwenhuysen, Ignace Vergote, Robert A Vierkant, Shan Wang-Gohrke, Christine S Walsh, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R. Wilkens, Yin Ling Woo, Xifeng Wu, Anna H Wu, Hannah P Yang, Wei Zheng, Argyrios Ziogas, Thomas A Sellers, Alvaro N.A. Monteiro, Matthew L Freedman, Simon A Gayther, Paul D P Pharoah, on behalf of the Australian Cancer Study, on behalf of the Australian Ovarian Cancer Study Group

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21 Citations (Scopus)

Abstract

Background: 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. Methods: 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). Results: 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. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

Original languageEnglish
Pages (from-to)1574-1584
Number of pages11
JournalCancer Epidemiology, Biomarkers & Prevention
Volume24
Issue number10
DOIs
Publication statusPublished - Oct 2015
Externally publishedYes

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