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

Kar SP, Adler E, Tyrer J, Hazelett D, Anton-Culver H, Bandera EV, Beckmann M, Berchuck A, Bogdanova N, Brinton L, Butzow R, Campbell I, Carty K, Chang-Claude J, Cook LS, Cramer DW, Cunningham JM, Dansonka-Mieszkowska A, Doherty JA, Doerk T, Duerst M, Eccles D, Fasching P, Flanagan J, Gentry-Maharaj A, Glasspool R, Goode EL, Goodman MT, Gronwald J, Heitz F, Hildebrandt MAT, Hogdall E, Hogdall CK, Huntsman DG, Jensen A, Karlan BY, Kelemen LE, Kiemeney LA, Kjaer SK, Kupryjanczyk J, Lambrechts D, Levine DA, Li Q, Lissowska J, Lu KH, Lubinski J, Massuger LFAG, Mcguire V, Mcneish I, Menon U, Modugno F, Monteiro AN, Moysich KB, Ness RB, Nevanlinna H, Paul J, Pearce CL, Pejovic T, Permuth JB, Phelan C, Pike MC, Poole EM, Ramus SJ, Risch HA, Rossing MA, Salvesen HB, Schildkraut JM, Sellers TA, Sherman M, Siddiqui N, Sieh W, Song H, Southey M, Terry KL, Tworoger SS, Walsh C, Wentzensen N, Whittemore AS, Wu AH, Yang H, Zheng W, Ziogas A, Freedman ML, Gayther SA, Pharoah PDP, Lawrenson K (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 116

Pages Range: 524-535

Journal Issue: 4

DOI: 10.1038/bjc.2016.426

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 (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.

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Involved external institutions

University of Cambridge United Kingdom (GB) University of Southern California (USC) United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) University of California Irvine United States (USA) (US) Rutgers Cancer Institute of New Jersey United States (USA) (US) Duke University United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) National Cancer Institute (NCI) United States (USA) (US) Helsingin yliopisto / University of Helsinki Finland (FI) Peter MacCallum Cancer Centre Australia (AU) Beatson West of Scotland Cancer Centre (BWSCC) United Kingdom (GB) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) University of New Mexico (UNM) / Universidad de Nuevo México United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) Mayo Clinic United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Dartmouth College United States (USA) (US) Universitätsklinikum Jena Germany (DE) University of Southampton United Kingdom (GB) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) University College London (UCL) United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Kliniken Essen-Mitte Germany (DE) University of Texas MD Anderson Cancer Center United States (USA) (US) Danish Cancer Society Research Center Denmark (DK) University of Copenhagen Denmark (DK) British Columbia Cancer Agency Canada (CA) Medical University of South Carolina (MUSC) United States (USA) (US) Radboud University Nijmegen Netherlands (NL) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Memorial Sloan Kettering Cancer Center United States (USA) (US) Dana–Farber Cancer Institute United States (USA) (US) Stanford University United States (USA) (US) University of Glasgow United Kingdom (GB) University of Pittsburgh United States (USA) (US) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS) Finland (FI) Oregon Health and Science University (OSHU) United States (USA) (US) University of New South Wales (UNSW) Australia (AU) Yale University United States (USA) (US) Fred Hutchinson Cancer Research Center Canada (CA) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Glasgow Royal Infirmary (GRI) United Kingdom (GB) The University of Melbourne Australia (AU) Vanderbilt University United States (USA) (US)

How to cite

APA:

Kar, S.P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E.V.,... 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://dx.doi.org/10.1038/bjc.2016.426

MLA:

Kar, Siddhartha P., et al. "Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci." British Journal of Cancer 116.4 (2017): 524-535.

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