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

Kar, S. P. et al. (2017) Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci. British Journal of Cancer, 116(4), pp. 524-535. (doi: 10.1038/bjc.2016.426) (PMID:28103614) (PMCID:PMC5318969)

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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 (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<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 (PGSEA=0.025) and IGROV1 (PGSEA=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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Glasspool, Dr Rosalind and Paul, Mr James and Carty, Mrs Karen and Mcneish, Professor Iain
Authors: 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., Dörk, T., Dürst, M., Eccles, D., Fasching, P. A., Flanagan, J., Gentry-Maharaj, A., Glasspool, R., Goode, E. L., Goodman, M. T., Gronwald, J., Heitz, F., Hildebrandt, M. A.T., Høgdall, E., Høgdall, C. K., Huntsman, D. G., Jensen, A., Karlan, B. Y., Kelemen, L. E., Kiemeney, L. A., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Levine, D. A., Li, Q., Lissowska, J., Lu, K. H., Lubiński, J., Massuger, L. F.A.G., McGuire, V., McNeish, I., Menon, U., Modugno, F., Monteiro, A. N., Moysich, K. B., Ness, R. B., Nevanlinna, H., Paul, J., Pearce, C. L., Pejovic, T., Permuth, J. B., Phelan, C., Pike, M. C., Poole, E. M., Ramus, S. J., Risch, H. A., Rossing, M. A., Salvesen, H. B., Schildkraut, J. M., Sellers, T. A., Sherman, M., Siddiqui, N., Sieh, W., Song, H., Southey, M., Terry, K. L., Tworoger, S. S., Walsh, C., Wentzensen, N., Whittemore, A. S., Wu, A. H., Yang, H., Zheng, W., Ziogas, A., Freedman, M. L., Gayther, S. A., Pharoah, P. D.P., and Lawrenson, K.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:British Journal of Cancer
Publisher:Cancer Research UK
ISSN (Online):1532-1827
Published Online:19 January 2017
Copyright Holders:Copyright © 2017 Cancer Research UK
First Published:First published in British Journal of Cancer 116(4): 524-535
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
415281Pharmacodynamics and drug resistanceRobert BrownCancer Research UK (CAN-RES-UK)C536/A6689RI CANCER SCIENCES