Identification of a Locus Near <i>ULK1</i> Associated With Progression-Free Survival in Ovarian Cancer
Michael C. Quinn, Karen McCue, Wei Shi, Sharon E. Johnatty, Jonathan Beesley, Andrew Civitarese, Tracy A. O’Mara, Dylan M. Glubb, Jonathan P. Tyrer, Sebastian M. Armasu, Jue‐Sheng Ong, Puya Gharahkhani, Yi Lu, Bo Gao, Ann‐Marie Patch, Peter A. Fasching, Matthias W. Beckmann, Diether Lambrechts, Ignace Vergote, Digna R. Velez Edwards, Alicia Beeghly‐Fadiel, Javier Benı́tez, María J. García, Marc T. Goodman, Thilo Dörk, Matthias Dürst, Francesmary Modugno, Kirsten B. Moysich, Andreas du Bois, Jacobus Pfisterer, Klaus Bauman, Beth Y. Karlan, Jenny Lester, Julie M. Cunningham, Melissa C. Larson, Bryan M. McCauley, Susanne K. Kjær, Allan Jensen, Claus Høgdall, Estrid Høgdall, Joellen M. Schildkraut, Marjorie J. Riggan, Andrew Berchuck, Daniel W. Cramer, Kathryn L. Terry, Line Bjørge, Penelope M. Webb, Michael Friedländer, Tanja Pejović, Melissa Moffitt, Rosalind Glasspool, Taymaa May, Gabrielle Ene, David G. Huntsman, Michelle Woo, Michael E. Carney, Samantha Hinsley, Florian Heitz, Sián Fereday, Catherine J. Kennedy, Stacey L. Edwards, Stacey J. Winham, Anna DeFazio, Paul D.P. Pharoah, Ellen L. Goode, Stuart MacGregor, Georgia Chenevix‐Trench
Abstract
Abstract Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P &lt; 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604