||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 LF, 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 YE, Berchuck A, MacGregor S, Pharoah PD, Goode EL, deFazio A, Webb PM, Chenevix-Trench G, Australian Ovarian Cancer Study Group
||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.