Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer
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.
See related commentary by Peres and Monteiro, p. 1604
Funding
Cancer Research UK Grant C536/A6689Collaborative Genetic Study of Ovarian Cancer RiskCancer Research UK (CRUK) Grant C12292/A11174Dana-Farber/Harvard Cancer Center Ovarian Cancer SPORECancer Research UK Grant C1287/A 10710Elucidating Loci Involved in Prostate Cancer SuceptibilityThe Molecular Epidemiology Of Ovarian CancerRelating Molecular Subgroups of Endometriosis-Associated Ovarian Cancers to Survival and RiskFollow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)The Mitochondrial Genome and Ovarian Cancer RiskDiscovery, Biology and Risk of Inherited Variants in Breast CancerCancer Research UK (CRUK) Grant C1281/A12014UCLA Clinical and Translational Science InstituteRegulatory T Cell Function in Ovarian CancerCancer Research UK Grant 16561Cancer Research UK Grant C536/A13086Project 1General Clinical Research CenterInflammation and Ovarian CancerCancer Research UK (CRUK) Grant C5047/A10692UCLA Clinical and Translational Science InstituteOVARIAN CANCER RISK AND SURVIVAL IN BRCA CARRIERSCancer Research UK (CRUK) Grant C5047/A8384PathologyA genome-wide association study for breast cancer in BRCA1 mutation carriersGenes, Hormones & Environment in an Ovarian Cancer ModelGenetic Variation in the NF-kappaB Pathway and Ovarian Cancer EtiologyCancer Risk Assessment, Early Detection, and Interception Research ProgramCancer Research UK (CRUK) Grant C5047/A15007Cancer Research UK (CRUK) Grant C1287/A10118Project 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian CancerU.S. National Institutes of Health 2 Grant CA1×01HG007491-01Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)The Mitochondrial Genome and Ovarian Cancer RiskCollaborative Genetic Study of Ovarian Cancer RiskCanadian Institutes of Health 3 Research FundingOvarian Cancer Research Fund FundingEuropean Community's Seventh Framework Programme Grant 223175European Community's Seventh Framework Programme Grant HEALTH-F2-2009-223175European Community's Seventh Framework Programme Grant C1287/A10118European Community's Seventh Framework Programme Grant C1287/A 10710European Community's Seventh Framework Programme Grant C12292/A11174European Community's Seventh Framework Programme Grant C1281/A12014European Community's Seventh Framework Programme Grant C5047/A8384European Community's Seventh Framework Programme Grant C5047/A15007European Community's Seventh Framework Programme Grant C5047/A10692European Community's Seventh Framework Programme Grant C8197/A16565A genome-wide association study for breast cancer in BRCA1 mutation carriersElucidating Loci Involved in Prostate Cancer SuceptibilityPost-Cancer GWAS initiative Grant 1U19 CA148065,Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)Department of Defence Grant W81XWH-10-1-0341Canadian Institutes of Health Research FundingCIHR Team in Familial Risks of Breast Cancer FundingKomen Foundation for the Cure FundingBreast Cancer Research Foundation FundingMedical Research and Materiel Command Grant DAMD17-01-1-0729National Health & Medical Research Council of Australia Grant 199600National Health & Medical Research Council of Australia Grant 400281Cancer Councils of New South Wales FundingELAN Funds of the University of Erlangen-Nuremberg FundingNationaal Kankerplan FundingNIH FundingNational Center for Advancing Translational Sciences Grant ULTR000445National Center for Advancing Translational Sciences Grant PI 12/01319National Center for Advancing Translational Sciences Grant R01-CA58598In vitro and In Vivo screening of chemopreventive agentsCancer Genetic Network (CGN)NCI Grant K07-CA80668Inflammation and Ovarian CancerProject 1Regulatory T Cell Function in Ovarian CancerMedical Research and Materiel Command Grant DAMD17-02-1-0669National Center for Research Resources FundingGeneral Clinical Research Center Grant MO1- RR000056Women's Cancer Program FundingAmerican Cancer Society Early Detection Professorship Grant 120950-SIOP-06-258-06-COUNNational Center for Advancing Translational Sciences Grant UL1TR000124Mayo Clinic Case-Only Ovarian Cancer Study FundingMayo Clinic Ovarian Cancer Case-Control Study FundingGenetic Variation in the NF-kappaB Pathway and Ovarian Cancer EtiologyNIH Grant P30-CA15083Project 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian CancerMayo Foundation Fundinginnesota Ovarian Cancer Alliance Grant R01- CA61107NCI Grant 94 222 52North Carolina Ovarian Cancer Study FundingNIH Grant R01-CA76016Department of Defense Grant DAMD17-02-1-0666New England-based Case-Control Study of Ovarian Cancer FundingGenes, Hormones & Environment in an Ovarian Cancer ModelDana-Farber/Harvard Cancer Center Ovarian Cancer SPOREDepartment of Defense CDMRP Grant W81XWH-10-1-0280University of Bergen FundingHaukeland University Hospital FundingOvarian Cancer Prognosis and Lifestyle Study FundingNational Health and Medical Research Council (NHMRC) Grant APP1025142National Health and Medical Research Council (NHMRC) Grant APP1120431National Health and Medical Research Council of Australia FundingScottish Randomised Trial in Ovarian Cancer FundingImperial Experimental Cancer Research Centre Grant C1312/A15589Princess Margaret Cancer Centre FundingPrincess Margaret Cancer Centre Foundation-Bridge FundingGynaecological Oncology Biobank at Westmead FundingAustralian National Health and Medical Research Council Enabling Grants Grant 310670Australian National Health and Medical Research Council Enabling Grants Grant 628903Australian National Health and Medical Research Council Enabling Grants Grant 12/RIG/1-17Australian National Health and Medical Research Council Enabling Grants Grant 15/RIG/1-16Australian National Health and Medical Research Council Enabling Grants Grant APP1158083Australian National Health and Medical Research Council Enabling Grants Grant 1113867University of Sydney Cancer Research Fund FundingAmerican Cancer Society Early Detection Professorship Grant SIOP-06-258-01-COUNNCI Funding