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

Journal article

Publication Details

Author(s): 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
Journal: British Journal of Cancer
Publication year: 2017
Volume: 116
Journal issue: 4
Pages range: 524-535
ISSN: 0007-0920


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.

FAU Authors / FAU Editors

Beckmann, Matthias Prof. Dr.
Lehrstuhl für Geburtshilfe und Frauenheilkunde
Fasching, Peter PD Dr.
Professur für Translationale Frauenheilkunde und Geburtshilfe

External institutions with authors

Beatson West of Scotland Cancer Centre (BWSCC)
Brigham and Women's Hospital (BWH)
British Columbia Cancer Agency
Cedars-Sinai Medical Center
Dana–Farber Cancer Institute
Danish Cancer Society Research Center
Dartmouth College
Deutsches Krebsforschungszentrum (DKFZ)
Duke University
Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB)
Fred Hutchinson Cancer Research Center
Glasgow Royal Infirmary (GRI)
Haukeland University Hospital / Haukeland universitetssykehus
Helsingin yliopisto / University of Helsinki
Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS)
H. Lee Moffitt Cancer Center & Research Institute
Imperial College London / The Imperial College of Science, Technology and Medicine
Kliniken Essen-Mitte
Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie
Mayo Clinic
Medical University of South Carolina (MUSC)
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Memorial Sloan Kettering Cancer Center
National Cancer Institute (NCI)
Oregon Health and Science University (OSHU)
Peter MacCallum Cancer Centre
Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU)
Radboud University Nijmegen
Roswell Park Cancer Institute
Rutgers Cancer Institute of New Jersey
Stanford University
The University of Melbourne
Universitätsklinikum Jena
University College London (UCL)
University of California Irvine
University of Cambridge
University of Copenhagen
University of Glasgow
University of New Mexico
University of New South Wales (UNSW)
University of Pittsburgh
University of Southampton
University of Southern California (USC)
University of Texas MD Anderson Cancer Center
Vanderbilt University

How to cite

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

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.


Last updated on 2019-26-03 at 06:23