Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium.
PURPOSE: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. EXPERIMENTAL DESIGN: 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. RESULTS: 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)). CONCLUSIONS: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.
Johnatty, SE; Tyrer, JP; Kar, S; Beesley, J; Lu, Y; Gao, B; Fasching, PA; Hein, A; Ekici, AB; Beckmann, MW; 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; Lubiński, 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; AGO Study Group, ; Karlan, BY; Walsh, C; Lester, J; Orsulic, S; Winham, SJ; Earp, M; Larson, MC; Fogarty, ZC; Høgdall, 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; Høgdall, C; Lundvall, L; McNeish, I; Paul, J; Carty, K; Siddiqui, N; Glasspool, R; Sellers, T; Kennedy, C; Chiew, Y-E; Berchuck, A; MacGregor, S; Pharoah, PDP; Goode, EL; deFazio, A; Webb, PM; Chenevix-Trench, G; Australian Ovarian Cancer Study Group,
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