Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Johnatty SE, Tyrer JP, Kar S, Beesley J, Lu Y, Gao B, Fasching P, Hein A, Ekici AB, Beckmann M, Lambrechts D, Van Nieuwenhuysen E, Vergote I, Lambrechts S, Rossing MA, Doherty JA, Chang-Claude J, Modugno F, Ness RB, Moysich KB, Levine DA, Kiemeney LA, Massuger LFAG, Gronwald J, Lubinski J, Jakubowska A, Cybulski C, Brinton L, Lissowska J, Wentzensen N, Song H, Rhenius V, Campbell I, Eccles D, Sieh W, Whittemore AS, Mcguire V, Rothstein JH, Sutphen R, Anton-Culver H, Ziogas A, Gayther SA, Gentry-Maharaj A, Menon U, Ramus SJ, Pearce CL, Pike MC, Stram DO, Wu AH, Kupryjanczyk J, Dansonka-Mieszkowska A, Rzepecka IK, Spiewankiewicz B, Goodman MT, Wilkens LR, Carney ME, Thompson PJ, Heitz F, Du Bois A, Schwaab I, Harter P, Pisterer J, Hillemanns P, Karlan BY, Walsh C, Lester J, Orsulic S, Winham SJ, Earp M, Larson MC, Fogarty ZC, Hogdall E, Jensen A, Kjaer SK, Fridley BL, Cunningham JM, Vierkant RA, Schildkraut JM, Iversen ES, Terry KL, Cramer DW, Bandera EV, Orlow I, Pejovic T, Bean Y, Hogdall C, Lundvall L, Mcneish I, Paul J, Carty K, Siddiqui N, Glasspool R, Sellers T, Kennedy C, Chiew YE, Berchuck A, Macgregor S, Pharoah PDP, Goode EL, Defazio A, Webb PM, Chenevix-Trench G (2015)


Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 21

Pages Range: 5264-76

Journal Issue: 23

DOI: 10.1158/1078-0432.CCR-15-0632

Abstract

Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with >=4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.Five SNPs were significantly associated (P <= 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P <= 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA <=6 × 10(-3)).We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264-76. ©2015 AACR.

Authors with CRIS profile

Involved external institutions

Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) BE Belgium (BE) Kliniken Essen-Mitte DE Germany (DE) Duke University US United States (USA) (US) Mayo Clinic US United States (USA) (US) Cedars-Sinai Medical Center US United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) National Cancer Institute (NCI) US United States (USA) (US) University College London (UCL) GB United Kingdom (GB) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) University of Cambridge GB United Kingdom (GB) Westmead Hospital AU Australia (AU) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) Fred Hutchinson Cancer Research Center CA Canada (CA) Dartmouth College US United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) University of Pittsburgh US United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) US United States (USA) (US) Roswell Park Cancer Institute US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) Radboud University Nijmegen NL Netherlands (NL) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) PL Poland (PL) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie PL Poland (PL) Peter MacCallum Cancer Centre AU Australia (AU) University of Southampton GB United Kingdom (GB) Stanford University US United States (USA) (US) University of South Florida (USF) US United States (USA) (US) University of California Irvine US United States (USA) (US) University of Southern California (USC) US United States (USA) (US) Institute for Oncology Ljubljana (OIL) SI Slovenia (SI) University of Hawaii (U.H.) US United States (USA) (US) Institut für Humangenetik Wiesbaden DE Germany (DE) Danish Cancer Society DK Denmark (DK) University of Kansas (KU) US United States (USA) (US) Brigham and Women's Hospital (BWH) US United States (USA) (US) The State University of New Jersey (Rutgers) US United States (USA) (US) Oregon Health and Science University (OSHU) US United States (USA) (US) University of Copenhagen DK Denmark (DK) University of Glasgow GB United Kingdom (GB) Beatson West of Scotland Cancer Centre (BWSCC) GB United Kingdom (GB) Glasgow Royal Infirmary (GRI) GB United Kingdom (GB)

How to cite

APA:

Johnatty, S.E., Tyrer, J.P., Kar, S., Beesley, J., Lu, Y., Gao, B.,... Chenevix-Trench, G. (2015). Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium. Clinical Cancer Research, 21(23), 5264-76. https://dx.doi.org/10.1158/1078-0432.CCR-15-0632

MLA:

Johnatty, Sharon E., et al. "Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium." Clinical Cancer Research 21.23 (2015): 5264-76.

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