Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk
Authors: Kar Siddhartha P. , Tyrer Jonathan P. , Li Qiyuan , Lawrenson Kate , Aben Katja K.H. , Anton-Culver Hoda , Antonenkova Natalia , Chenevix-Trench Georgia ,   on behalf of the Australian Cancer Study,   and on behalf of the Australian Ovarian Cancer Study Group, Baker Helen , Bandera Elisa V. , Bean Yukie T. , Beckmann Matthias W. , Berchuck Andrew , Bisogna Maria , Bjørge Line , Bogdanova Natalia , Brinton Louise , Brooks-Wilson Angela , Butzow Ralf , Campbell Ian , Carty Karen , Chang-Claude Jenny , Chen Yian Ann , Chen Zhihua , Cook Linda S. , Cramer Daniel , Cunningham Julie M. , Cybulski Cezary , Dansonka-Mieszkowska Agnieszka , Dennis Joe , Dicks Ed , Doherty Jennifer A. , Dörk Thilo , du Bois Andreas , Dürst Matthias , Eccles Diana , Easton Douglas F. , Edwards Robert P. , Ekici Arif B. , Fasching Peter A. , Fridley Brooke L. , Gao Yu-Tang , Gentry-Maharaj Aleksandra , Giles Graham G. , Glasspool Rosalind , Goode Ellen L. , Goodman Marc T. , Grownwald Jacek , Harrington Patricia , Harter Philipp , Hein Alexander , Heitz Florian , Hildebrandt Michelle A.T. , Hillemanns Peter , Hogdall Estrid , Hogdall Claus K. , Hosono Satoyo , Iversen Edwin S. , Jakubowska Anna , Paul James , Jensen Allan , Ji Bu-Tian , Karlan Beth Y. , Kjaer Susanne K. , Kelemen Linda E. , Kellar Melissa , Kelley Joseph , Kiemeney Lambertus A. , Krakstad Camilla , Kupryjanczyk Jolanta , Lambrechts Diether , Lambrechts Sandrina , Le Nhu D. , Lee Alice W. , Lele Shashi , Leminen Arto , Lester Jenny , Levine Douglas A. , Liang Dong , Lissowska Jolanta , Lu Karen , Lubinski Jan , Lundvall Lene , Massuger Leon , Matsuo Keitaro , McGuire Valerie , McLaughlin John R. , McNeish Iain A. , Menon Usha , Modugno Francesmary , Moysich Kirsten B. , Narod Steven A. , Nedergaard Lotte , Ness Roberta B. , Nevanlinna Heli , Odunsi Kunle , Olson Sara H. , Orlow Irene , Orsulic Sandra , Weber Rachel Palmieri , Pearce Celeste Leigh , Pejovic Tanja , Pelttari Liisa M. , Permuth-Wey Jennifer , Phelan Catherine M. , Pike Malcolm C. , Poole Elizabeth M. , Ramus Susan J. , Risch Harvey A. , Rosen Barry , Rossing Mary Anne , Rothstein Joseph H. , Rudolph Anja , Runnebaum Ingo B. , Rzepecka Iwona K. , Salvesen Helga B. , Schildkraut Joellen M. , Schwaab Ira , Shu Xiao-Ou , Shvetsov Yurii B. , Siddiqui Nadeem , Sieh Weiva , Song Honglin , Southey Melissa C. , Sucheston-Campbell Lara E. , Tangen Ingvild L. , Teo Soo-Hwang , Terry Kathryn L. , Thompson Pamela J. , Timorek Agnieszka , Tsai Ya-Yu , Tworoger Shelley S. , van Altena Anne M. , Van Nieuwenhuysen Els , Vergote Ignace , Vierkant Robert A. , Wang-Gohrke Shan , Walsh Christine , Wentzensen Nicolas , Whittemore Alice S. , Wicklund Kristine G. , Wilkens Lynne R. , Woo Yin-Ling , Wu Xifeng , Wu Anna , Yang Hannah , Zheng Wei , Ziogas Argyrios , Sellers Thomas A. , Monteiro Alvaro N.A. , Freedman Matthew L. , Gayther Simon A. , Pharoah Paul D.P. 
Published: July 2015

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 &lt; 0.05 and FDR &lt; 0.05). These results were replicated (P &lt; 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. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.