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Review
. 2015 Oct;24(10):1574-84.
doi: 10.1158/1055-9965.EPI-14-1270. Epub 2015 Jul 24.

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

Siddhartha P Kar  1 , Jonathan P Tyrer  2 , Qiyuan Li  3 , Kate Lawrenson  4 , Katja K H Aben  5 , Hoda Anton-Culver  6 , Natalia Antonenkova  7 , Georgia Chenevix-Trench  8 ; Australian Cancer Study; Australian Ovarian Cancer Study Group; Helen Baker  2 , Elisa V Bandera  9 , Yukie T Bean  10 , Matthias W Beckmann  11 , Andrew Berchuck  12 , Maria Bisogna  13 , Line Bjørge  14 , Natalia Bogdanova  15 , Louise Brinton  16 , Angela Brooks-Wilson  17 , Ralf Butzow  18 , Ian Campbell  19 , Karen Carty  20 , Jenny Chang-Claude  21 , Yian Ann Chen  22 , Zhihua Chen  22 , Linda S Cook  23 , Daniel Cramer  24 , Julie M Cunningham  25 , Cezary Cybulski  26 , Agnieszka Dansonka-Mieszkowska  27 , Joe Dennis  28 , Ed Dicks  2 , Jennifer A Doherty  29 , Thilo Dörk  15 , Andreas du Bois  30 , Matthias Dürst  31 , Diana Eccles  32 , Douglas F Easton  33 , Robert P Edwards  34 , Arif B Ekici  35 , Peter A Fasching  36 , Brooke L Fridley  37 , Yu-Tang Gao  38 , Aleksandra Gentry-Maharaj  39 , Graham G Giles  40 , Rosalind Glasspool  20 , Ellen L Goode  41 , Marc T Goodman  42 , Jacek Grownwald  26 , Patricia Harrington  2 , Philipp Harter  30 , Alexander Hein  11 , Florian Heitz  30 , Michelle A T Hildebrandt  43 , Peter Hillemanns  44 , Estrid Hogdall  45 , Claus K Hogdall  46 , Satoyo Hosono  47 , Edwin S Iversen  48 , Anna Jakubowska  26 , James Paul  20 , Allan Jensen  49 , Bu-Tian Ji  16 , Beth Y Karlan  50 , Susanne K Kjaer  51 , Linda E Kelemen  52 , Melissa Kellar  10 , Joseph Kelley  53 , Lambertus A Kiemeney  54 , Camilla Krakstad  14 , Jolanta Kupryjanczyk  27 , Diether Lambrechts  55 , Sandrina Lambrechts  56 , Nhu D Le  57 , Alice W Lee  4 , Shashi Lele  58 , Arto Leminen  59 , Jenny Lester  50 , Douglas A Levine  13 , Dong Liang  60 , Jolanta Lissowska  61 , Karen Lu  62 , Jan Lubinski  26 , Lene Lundvall  46 , Leon Massuger  63 , Keitaro Matsuo  64 , Valerie McGuire  65 , John R McLaughlin  66 , Iain A McNeish  67 , Usha Menon  39 , Francesmary Modugno  68 , Kirsten B Moysich  58 , Steven A Narod  69 , Lotte Nedergaard  70 , Roberta B Ness  71 , Heli Nevanlinna  59 , Kunle Odunsi  72 , Sara H Olson  73 , Irene Orlow  73 , Sandra Orsulic  50 , Rachel Palmieri Weber  74 , Celeste Leigh Pearce  4 , Tanja Pejovic  10 , Liisa M Pelttari  59 , Jennifer Permuth-Wey  75 , Catherine M Phelan  75 , Malcolm C Pike  76 , Elizabeth M Poole  77 , Susan J Ramus  4 , Harvey A Risch  78 , Barry Rosen  79 , Mary Anne Rossing  80 , Joseph H Rothstein  65 , Anja Rudolph  21 , Ingo B Runnebaum  31 , Iwona K Rzepecka  27 , Helga B Salvesen  14 , Joellen M Schildkraut  81 , Ira Schwaab  82 , Xiao-Ou Shu  83 , Yurii B Shvetsov  84 , Nadeem Siddiqui  85 , Weiva Sieh  65 , Honglin Song  2 , Melissa C Southey  86 , Lara E Sucheston-Campbell  58 , Ingvild L Tangen  14 , Soo-Hwang Teo  87 , Kathryn L Terry  24 , Pamela J Thompson  42 , Agnieszka Timorek  88 , Ya-Yu Tsai  75 , Shelley S Tworoger  77 , Anne M van Altena  63 , Els Van Nieuwenhuysen  56 , Ignace Vergote  56 , Robert A Vierkant  41 , Shan Wang-Gohrke  89 , Christine Walsh  50 , Nicolas Wentzensen  16 , Alice S Whittemore  65 , Kristine G Wicklund  90 , Lynne R Wilkens  84 , Yin-Ling Woo  91 , Xifeng Wu  43 , Anna Wu  4 , Hannah Yang  16 , Wei Zheng  83 , Argyrios Ziogas  6 , Thomas A Sellers  75 , Alvaro N A Monteiro  75 , Matthew L Freedman  3 , Simon A Gayther  4 , Paul D P Pharoah  33
Affiliations
Review

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

Siddhartha P Kar et al. Cancer Epidemiol Biomarkers Prev. 2015 Oct.

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.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

Dr. Fasching reports receiving commercial research support from Amgen and Novartis and honoraria from speakers’ bureaus from Amgen, Novartis, Pfizer, Celgene, Roche, and GSK. Dr. Menon reports having a commercial research grant from and ownership interest in Abcodia.

Figures

Figure 1
Figure 1
Outline of steps involved in the integrated analysis of GWAS and tissue-specific expression data sets to identify, replicate and computationally follow-up gene networks associated with serous EOC susceptibility.
Figure 2
Figure 2
Cytoscape visualization of the combined network. Hub TF genes of the six significant networks underlying the combined network are outlined in green. Candidate genes at genome-wide significant risk loci other than the input hub loci (2q31 and 17q21.32) are outlined in blue. Nodes are colored according to the P-value of the most significant intragenic SNP in the GWAS meta-analysis (uncorrected for the number of intragenic SNPs). Diamond shaped genes have P < 0.05 after applying the modified Sidak correction.
See this image and copyright information in PMC

References

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