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

Sharon E. Johnatty, on behalf of the Australian Ovarian Cancer Study Group, Jonathan P. Tyrer, Siddhartha Kar, Jonathan Beesley, Yi Lu, Bo Gao, Peter A. Fasching, Alexander Hein, Arif B. Ekici, Matthias W. Beckmann, Diether Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Sandrina Lambrechts, Mary Anne Rossing, Jennifer A. Doherty, Jenny Chang-Claude, Francesmary Modugno, Roberta B. Ness, Kirsten B. Moysich, Douglas A. Levine, Lambertus A. Kiemeney, Leon F.A.G. Massuger, Jacek Gronwald, Jan Lubiński, Anna Jakubowska, Cezary Cybulski, Louise Brinton, Jolanta Lissowska, Nicolas Wentzensen, Honglin Song, Valerie Rhenius, Ian Campbell, Diana Eccles, Weiva Sieh, Alice S. Whittemore, Valerie McGuire, Joseph H. Rothstein, Rebecca Sutphen, Hoda Anton-Culver, Argyrios Ziogas, Simon A. Gayther, Aleksandra Gentry-Maharaj, Usha Menon, Susan J. Ramus, Celeste L. Pearce, Malcolm C. Pike, Daniel O. Stram, Anna H. Wu, Jolanta Kupryjanczyk, Agnieszka Dansonka-Mieszkowska, Iwona K. Rzepecka, Beata Spiewankiewicz, Marc T. Goodman, Lynne R. Wilkens, Michael E. Carney, Pamela J. Thompson, Florian Heitz, Andreas du Bois, Ira Schwaab, Philipp Harter, Jacobus Pisterer, Peter Hillemanns, on behalf of the AGO Study Group, Beth Y. Karlan, Christine Walsh, Jenny Lester, Sandra Orsulic, Stacey J. Winham, Madalene Earp, Melissa C. Larson, Zachary C. Fogarty, Estrid Høgdall, Allan Jensen, Susanne Kruger Kjaer, Brooke L. Fridley, Julie M. Cunningham, Robert A. Vierkant, Joellen M. Schildkraut, Edwin S. Iversen, Kathryn L. Terry, Daniel W. Cramer, Elisa V. Bandera, Irene Orlow, Tanja Pejovic, Yukie Bean, Claus Høgdall, Lene Lundvall, Ian McNeish, James Paul, Karen Carty, Nadeem Siddiqui, Rosalind Glasspool, Thomas Sellers, Catherine Kennedy, Yoke-Eng Chiew, Andrew Berchuck, Stuart MacGregor, Paul D.P. Pharoah, Ellen L. Goode, Anna deFazio, Penelope M. Webb, Georgia Chenevix-Trench

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 ~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 firstline 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. Additionally 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≤1.0x10(-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 non-coding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1 and RP11-284F21.8 respectively (p≤7.1x10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary shows 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 HDL-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA≤6x10(-3)). We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.