Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

Siddhartha P. Kar, Emily Adler, Jonathan Tyrer, Dennis Hazelett, Hoda Anton-Culver, Elisa V. Bandera, Matthias W. Beckmann, Andrew Berchuck, Natalia Bogdanova, Louise Brinton, Ralf Butzow, Ian Campbell, Karen Carty, Jenny Chang-Claude, Linda S. Cook, Daniel W. Cramer, Julie M. Cunningham, Agnieszka Dansonka-Mieszkowska, Jennifer Anne Doherty, Thilo DörkMatthias Dürst, Diana Eccles, Peter A. Fasching, James Flanagan, Aleksandra Gentry-Maharaj, Rosalind Glasspool, Ellen L. Goode, Marc T. Goodman, Jacek Gronwald, Florian Heitz, Michelle A.T. Hildebrandt, Estrid Høgdall, Claus K. Høgdall, David G. Huntsman, Allan Jensen, Beth Y. Karlan, Linda E. Kelemen, Lambertus A. Kiemeney, Susanne K. Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Douglas A. Levine, Qiyuan Li, Jolanta Lissowska, Karen H. Lu, Jan Lubiński, Leon F.A.G. Massuger, Valerie McGuire, Iain McNeish, Usha Menon, Francesmary Modugno, Alvaro N. Monteiro, Kirsten B. Moysich, Roberta B. Ness, Heli Nevanlinna, James Paul, Celeste L. Pearce, Tanja Pejovic, Jennifer B. Permuth, Catherine Phelan, Malcolm C. Pike, Elizabeth M. Poole, Susan J. Ramus, Harvey A. Risch, Mary Anne Rossing, Helga B. Salvesen, Joellen M. Schildkraut, Thomas A. Sellers, Mark Sherman, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa Southey, Kathryn L. Terry, Shelley S. Tworoger, Christine Walsh, Nicolas Wentzensen, Alice S. Whittemore, Anna H. Wu, Hannah Yang, Wei Zheng, Argyrios Ziogas, Matthew L. Freedman, Simon A. Gayther, Paul D.P. Pharoah, Kate Lawrenson

Research output: Contribution to journalArticle

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Abstract

Background:Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis.Methods:All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals).Results:The PAX8-target gene set was ranked 1/615 in the discovery (P GSEA <0.001; FDR=0.21), 7/615 in the replication (P GSEA =0.004; FDR=0.37), and 1/615 in the combined (P GSEA <0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10 -5 (including six with P<5 × 10 -8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (P GSEA =0.025) and IGROV1 (P GSEA =0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation.Conclusions:Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.

Original languageEnglish (US)
Pages (from-to)524-535
Number of pages12
JournalBritish journal of cancer
Volume116
Issue number4
DOIs
StatePublished - Feb 14 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kar, S. P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E. V., Beckmann, M. W., Berchuck, A., Bogdanova, N., Brinton, L., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Cook, L. S., Cramer, D. W., Cunningham, J. M., Dansonka-Mieszkowska, A., Doherty, J. A., ... Lawrenson, K. (2017). Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci. British journal of cancer, 116(4), 524-535. https://doi.org/10.1038/bjc.2016.426