Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

• Type of Material: Article
• Authors: Michael CJ Quinn, QIMR Berghofer Medical Research Institute; Karen McCue, QIMR Berghofer Medical Research Institute; Wei Shi, QIMR Berghofer Medical Research Institute; Sharon E Johnatty, QIMR Berghofer Medical Research Institute; Jontahn Beesley, QIMR Berghofer Medical Research Institute; Andrew Civitarese, QIMR Berghofer Medical Research Institute; Tracy A O'Mara, QIMR Berghofer Medical Research Institute; Dylan M Glubb, QIMR Berghofer Medical Research Institute; Jonthan P Tyrer, University of Cambridge; Sebastian M Armasu, Mayo Clinic, Rochester; Jue-Sheng Ong, QIMR Berghofer Medical Research Institute; Puya Gharahkhani, QIMR Berghofer Medical Research Institute; Yi Lu, QIMR Berghofer Medical Research Institute; Ba Gao, Westmead Hospital; Ann-Marie Patch, QIMR Berghofer Medical Research Institute; Peter A Fasching, University of California Los Angeles; Mathhias W Beckmann, Friedrich-Alexander-University Erlangen-Nuremberg; Diether Lambrechts, Vesalius Research Center; Ignace Vergote, University Hospital Leuven; Digna Velez R Edwards, Vanderbilt University; Alicia Beeghly-Fadiel, Vanderbilt University; Javier Benitez, Spanish National Cancer Centre (CNIO); Maria J Garcia, Spanish National Cancer Centre (CNIO); Marc T Goodman, Cedars-Sinai Medical Center; Thilo Dörk, Hannover Medical School; Matthias Duerst, Friedrich Schiller University of Jena; Francesmary Modugno, University of Pittsburgh; Kirsten Moysich, Roswell Park Cancer Institute; Andreas du Bois, Kliniken Essen Mitte; Jacobus Pfisterer, Gynecologic Oncology Center; Klaus Bauman, Philipps University Marburg; Beth Y Karlan, University of California Los Angeles; Jenny Lester, University of California Los Angeles; Julie M Cunningham, Mayo Clinic, Rochester; Melissa C Larson, Mayo Clinic, Rochester; Bryan M McCauley, Mayo Clinic, Rochester; Susanne K Kjær, University of Copenhagen; Allan Jensen, Danish Cancer Society Research Center; Claus K Hogdall, University of Copenhagen; Estrid Hogdall, Danish Cancer Society Research Center; Joellen Schildkraut, Emory University; Marjorie J Riggan, Duke University Medical Center; Andrew Berchuck, Duke University Medical Center; Daniel W Cramer, Brigham and Women’s Hospital and Harvard Medical School; Kathryn L Terry, Brigham and Women’s Hospital and Harvard Medical Schoolp; Line Bjorge, Haukeland University Hospital; Penelope M Webb, QIMR Berghofer Medical Research Institute; Michael Friedlander, University of New South Wales; Tanja Pejovic, Oregon Health & Science University; Melissa Moffitt, Oregon Health & Science University; Rosalind Glasspool, .Beatson West of Scotland Cancer Centre; Taymaa May, University Health Network; Gabrielle E Ene, University Health Network; David G Huntsman, BC Cancer Agency and University of British Columbia; Michelle Woo, British Columbia Cancer Research; Michael E Carney, University of Hawaii; Samantha Hinsley, University of Glasgow; Florian Heitz, Kliniken Essen Mitte; Sian Fereday, .Peter MacCallum Cancer Centre; Catherine J Kennedy, Westmead Institute for Medical Research; Stacey L Edwards, QIMR Berghofer Medical Research Institute; Stacey J Winham, Mayo Clinic; Anna deFazio, Westmead Inst Med Res; Paul DP Pharoah, University of Cambridge; Ellen L Goode, Mayo Clinic, Rochester; Stuart MacGregor, QIMR Berghofer Medical Research Institute; Georgia Chenevix-Trench, QIMR Berghofer Medical Research Institute
• Language: English
• Date: 2021-09-01
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, American Association for Cancer Research
• Final Published Version (URL): http://dx.doi.org/10.1158/1055-9965.EPI-20-1817
• Title of Journal or Parent Work: CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
• Volume: 30
• Issue: 9
• Start Page: 1669
• End Page: 1680
• Keywords: EXPRESSION; POLYMORPHISMS; SEROUS OVARIAN; OUTCOMES; Public, Environmental & Occupational Health; AUTOPHAGY; METAANALYSIS; LIKELIHOOD; CONSORTIUM; Science & Technology; SUSCEPTIBILITY LOCI; Oncology; KINASE; Life Sciences & Biomedicine

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 < 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.