Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium
Authors: Johnatty Sharon E. , Tyrer Jonathan P. , Kar Siddhartha , Beesley Jonathan , Lu Yi , Gao Bo , Fasching Peter A. , Hein Alexander , Ekici Arif B. , Beckmann Matthias W. , Lambrechts Diether , Van Nieuwenhuysen Els , Vergote Ignace , Lambrechts Sandrina , Rossing Mary Anne , Doherty Jennifer A. , Chang-Claude Jenny , Modugno Francesmary , Ness Roberta B. , Moysich Kirsten B. , Levine Douglas A. , Kiemeney Lambertus A. , Massuger Leon F.A.G. , Gronwald Jacek , Lubiński Jan , Jakubowska Anna , Cybulski Cezary , Brinton Louise , Lissowska Jolanta , Wentzensen Nicolas , Song Honglin , Rhenius Valerie , Campbell Ian , Eccles Diana , Sieh Weiva , Whittemore Alice S. , McGuire Valerie , Rothstein Joseph H. , Sutphen Rebecca , Anton-Culver Hoda , Ziogas Argyrios , Gayther Simon A. , Gentry-Maharaj Aleksandra , Menon Usha , Ramus Susan J. , Pearce Celeste L. , Pike Malcolm C. , Stram Daniel O. , Wu Anna H. , Kupryjanczyk Jolanta , Dansonka-Mieszkowska Agnieszka , Rzepecka Iwona K. , Spiewankiewicz Beata , Goodman Marc T. , Wilkens Lynne R. , Carney Michael E. , Thompson Pamela J. , Heitz Florian , du Bois Andreas , Schwaab Ira , Harter Philipp , Pisterer Jacobus , Hillemanns Peter ,   on behalf of the AGO Study Group, Karlan Beth Y. , Walsh Christine , Lester Jenny , Orsulic Sandra , Winham Stacey J. , Earp Madalene , Larson Melissa C. , Fogarty Zachary C. , Høgdall Estrid , Jensen Allan , Kjaer Susanne Kruger , Fridley Brooke L. , Cunningham Julie M. , Vierkant Robert A. , Schildkraut Joellen M. , Iversen Edwin S. , Terry Kathryn L. , Cramer Daniel W. , Bandera Elisa V. , Orlow Irene , Pejovic Tanja , Bean Yukie , Høgdall Claus , Lundvall Lene , McNeish Ian , Paul James , Carty Karen , Siddiqui Nadeem , Glasspool Rosalind , Sellers Thomas , Kennedy Catherine , Chiew Yoke-Eng , Berchuck Andrew , MacGregor Stuart , Pharoah Paul D.P. , Goode Ellen L. , deFazio Anna , Webb Penelope M. , Chenevix-Trench Georgia 
Published: July 2015

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. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.