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Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk
- Kar, Siddhartha P;
- Tyrer, Jonathan P;
- Li, Qiyuan;
- Lawrenson, Kate;
- Aben, Katja KH;
- Anton-Culver, Hoda;
- Antonenkova, Natalia;
- Chenevix-Trench, Georgia;
- Study, on behalf of the Australian Cancer;
- Group, and on behalf of the Australian Ovarian Cancer Study;
- 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 AT;
- 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 NA;
- Freedman, Matthew L;
- Gayther, Simon A;
- Pharoah, Paul DP
- et al.
Published Web Location
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592449/pdf/nihms710805.pdfNo data is associated with this publication.
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.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.