Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Glubb DM, Johnatty SE, Quinn MCJ, O'Mara TA, Tyrer JP, Gao B, Fasching P, Beckmann M, Lambrechts D, Vergote I, Edwards DRV, Beeghly-Fadiel A, Benitez J, Garcia MJ, Goodman MT, Thompson PJ, Doerk T, Duerst M, Modungo F, Moysich K, Heitz F, Du Bois A, Pfisterer J, Hillemanns P, Karlan BY, Lester J, Goode EL, Cunningham JM, Winham SJ, Larson MC, Mccauley BM, Kjaer SK, Jensen A, Schildkraut JM, Berchuck A, Cramer DW, Terry KL, Salvesen HB, Bjorge L, Webb PM, Grant P, Pejovic T, Moffitt M, Hogdall CK, Hogdall E, Paul J, Glasspool R, Bernardini M, Tone A, Huntsman D, Woo M, Defazio A, Kennedy CJ, Pharoah PDP, Macgregor S, Chenevix-Trench G (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 8

Pages Range: 64670-64684

Journal Issue: 39

DOI: 10.18632/oncotarget.18501

Abstract

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.

Authors with CRIS profile

Involved external institutions

University of Cambridge United Kingdom (GB) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) British Columbia Cancer Agency Canada (CA) Brigham and Women's Hospital (BWH) United States (USA) (US) Kliniken Essen-Mitte Germany (DE) Mayo Clinic United States (USA) (US) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Roswell Park Cancer Institute United States (USA) (US) Vanderbilt University United States (USA) (US) Princess Margaret Cancer Centre / Princess Margaret Hospital Canada (CA) Friedrich-Schiller-Universität Jena Germany (DE) Danish Cancer Society Research Center Denmark (DK) Duke University United States (USA) (US) Oregon Health and Science University (OSHU) United States (USA) (US) Mercy Hospital for Women Australia (AU) Cedars-Sinai Medical Center United States (USA) (US) University of Copenhagen Denmark (DK) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) University of Pittsburgh United States (USA) (US) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) University of Sydney (USYD) Australia (AU) Westmead Hospital Australia (AU) Beatson West of Scotland Cancer Centre (BWSCC) United Kingdom (GB) University of Virginia (UVA) United States (USA) (US)

How to cite

APA:

Glubb, D.M., Johnatty, S.E., Quinn, M.C.J., O'Mara, T.A., Tyrer, J.P., Gao, B.,... Chenevix-Trench, G. (2017). Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci. Oncotarget, 8(39), 64670-64684. https://dx.doi.org/10.18632/oncotarget.18501

MLA:

Glubb, Dylan M., et al. "Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci." Oncotarget 8.39 (2017): 64670-64684.

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