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

Publication ,  Journal Article
Kar, SP; Tyrer, JP; Li, Q; Lawrenson, K; Aben, KKH; Anton-Culver, H; Antonenkova, N; Chenevix-Trench, G; Australian Cancer Study, ; Baker, H ...
Published in: Cancer Epidemiol Biomarkers Prev
October 2015

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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Published In

Cancer Epidemiol Biomarkers Prev

DOI

EISSN

1538-7755

Publication Date

October 2015

Volume

24

Issue

10

Start / End Page

1574 / 1584

Location

United States

Related Subject Headings

  • Transcription Factors
  • Risk Factors
  • Ovarian Neoplasms
  • Nuclear Proteins
  • Morbidity
  • Humans
  • Global Health
  • Genotype
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
 

Citation

APA
Chicago
ICMJE
MLA
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Kar, S. P., Tyrer, J. P., Li, Q., Lawrenson, K., Aben, K. K. H., Anton-Culver, H., … Pharoah, P. D. P. (2015). Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk. Cancer Epidemiol Biomarkers Prev, 24(10), 1574–1584. https://doi.org/10.1158/1055-9965.EPI-14-1270
Kar, Siddhartha P., Jonathan P. Tyrer, Qiyuan Li, Kate Lawrenson, Katja K. H. Aben, Hoda Anton-Culver, Natalia Antonenkova, et al. “Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.Cancer Epidemiol Biomarkers Prev 24, no. 10 (October 2015): 1574–84. https://doi.org/10.1158/1055-9965.EPI-14-1270.
Kar SP, Tyrer JP, Li Q, Lawrenson K, Aben KKH, Anton-Culver H, et al. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk. Cancer Epidemiol Biomarkers Prev. 2015 Oct;24(10):1574–84.
Kar, Siddhartha P., et al. “Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.Cancer Epidemiol Biomarkers Prev, vol. 24, no. 10, Oct. 2015, pp. 1574–84. Pubmed, doi:10.1158/1055-9965.EPI-14-1270.
Kar SP, Tyrer JP, Li Q, Lawrenson K, Aben KKH, Anton-Culver H, Antonenkova N, Chenevix-Trench G, Australian Cancer Study, Australian Ovarian Cancer Study Group, Baker H, Bandera EV, Bean YT, Beckmann MW, Berchuck A, Bisogna M, Bjørge L, Bogdanova N, Brinton L, Brooks-Wilson A, Butzow R, Campbell I, Carty K, Chang-Claude J, Chen YA, Chen Z, Cook LS, Cramer D, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Dicks E, Doherty JA, Dörk T, du Bois A, Dürst M, Eccles D, Easton DF, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gao Y-T, Gentry-Maharaj A, Giles GG, Glasspool R, Goode EL, Goodman MT, Grownwald J, Harrington P, Harter P, Hein A, Heitz F, Hildebrandt MAT, Hillemanns P, Hogdall E, Hogdall CK, Hosono S, Iversen ES, Jakubowska A, Paul J, Jensen A, Ji B-T, Karlan BY, Kjaer SK, Kelemen LE, Kellar M, Kelley J, Kiemeney LA, Krakstad C, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger L, Matsuo K, McGuire V, McLaughlin JR, McNeish IA, Menon U, Modugno F, Moysich KB, Narod SA, Nedergaard L, Ness RB, Nevanlinna H, Odunsi K, Olson SH, Orlow I, Orsulic S, Weber RP, Pearce CL, Pejovic T, Pelttari LM, Permuth-Wey J, Phelan CM, Pike MC, Poole EM, Ramus SJ, Risch HA, Rosen B, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schildkraut JM, Schwaab I, Shu X-O, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Sucheston-Campbell LE, Tangen IL, Teo S-H, Terry KL, Thompson PJ, Timorek A, Tsai Y-Y, Tworoger SS, van Altena AM, Van Nieuwenhuysen E, Vergote I, Vierkant RA, Wang-Gohrke S, Walsh C, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Woo Y-L, Wu X, Wu A, Yang H, Zheng W, Ziogas A, Sellers TA, Monteiro ANA, Freedman ML, Gayther SA, Pharoah PDP. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk. Cancer Epidemiol Biomarkers Prev. 2015 Oct;24(10):1574–1584.

Published In

Cancer Epidemiol Biomarkers Prev

DOI

EISSN

1538-7755

Publication Date

October 2015

Volume

24

Issue

10

Start / End Page

1574 / 1584

Location

United States

Related Subject Headings

  • Transcription Factors
  • Risk Factors
  • Ovarian Neoplasms
  • Nuclear Proteins
  • Morbidity
  • Humans
  • Global Health
  • Genotype
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease