Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk
Fulltext:
153484.pdf
Embargo:
until further notice
Size:
829.7Kb
Format:
PDF
Description:
Publisher’s version
Publication year
2015Author(s)
Source
Cancer Epidemiology, Biomarkers & Prevention, 24, 10, (2015), pp. 1574-84ISSN
Publication type
Article / Letter to editor
Display more detailsDisplay less details
Organization
Health Evidence
Urology
Gynaecology
Journal title
Cancer Epidemiology, Biomarkers & Prevention
Volume
vol. 24
Issue
iss. 10
Page start
p. 1574
Page end
p. 84
Subject
Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences; Radboudumc 17: Women's cancers RIMLS: Radboud Institute for Molecular Life SciencesAbstract
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. Cancer Epidemiol Biomarkers Prev; 24(10); 1574-84. (c)2015 AACR.
This item appears in the following Collection(s)
- Academic publications [246515]
- Electronic publications [134102]
- Faculty of Medical Sciences [93308]
Upload full text
Use your RU credentials (u/z-number and password) to log in with SURFconext to upload a file for processing by the repository team.