Journal article

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

Michael CJ 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 Show all

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION | AMER ASSOC CANCER RESEARCH | Published : 2021

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, an..

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Grants

Awarded by U.S. National Institutes of Health 2 (NIH)


Awarded by Canadian Institutes of Health 3 Research


Awarded by European Community


Awarded by Cancer Research UK


Awarded by NIH


Awarded by Post-Cancer GWAS initiative (GAME-ON initiative)


Awarded by Department of Defence


Awarded by U.S. Army Medical Research and Materiel Command


Awarded by National Health & Medical Research Council of Australia


Awarded by Cancer Foundation of Western Australia


Awarded by Vanderbilt CTSA grant from the NIH/National Center for Advancing Translational Sciences (NCATS)


Awarded by Instituto de Salud Carlos III


Awarded by Ministerio de Economia y Competitividad


Awarded by NCI


Awarded by US Army Medical Research andMateriel Command


Awarded by NIH/National Center for Research Resources/General Clinical Research Center


Awarded by American Cancer Society Early Detection Professorship


Awarded by National Center for Advancing Translational Sciences (NCATS)


Awarded by Danish Cancer Society, Copenhagen, Denmark


Awarded by Department of Defense


Awarded by National Health and Medical Research Council(NHMRC) of Australia


Awarded by Imperial Experimental Cancer Research Centre


Awarded by Australian National Health and Medical Research Council


Awarded by Cancer Institute NSW


Awarded by NHMRC


Awarded by NCI CCSG award


Awarded by Department of Defense CDMRP grant


Funding Acknowledgements

The OCAC (all authors, directly or indirectly through having samples genotyped on the iCOGS and/or OncoArray and/or having their data incorporated in the OCAC database) was funded through grants from the U.S. National Institutes of Health 2 (NIH) (CA1-01HG007491-01, U19-CA148112, R01-CA149429, and R01CA058598), Canadian Institutes of Health 3 Research (MOP-86727), and the Ovarian Cancer Research Fund (OCRF). Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175; COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the NIH (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.AUS studies (Australian Ovarian Cancer Study and the Australian Cancer Study; PI D. Bowtell and P.M. Webb) were funded by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729); National Health & Medical Research Council of Australia (199600 and 400281); Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania; and the Cancer Foundation of Western Australia (Multi-State Application Numbers 191, 211, and 182). The Bavarian study (BAV; PI P.A. Fasching) was supported by ELAN Funds of the University of Erlangen-Nuremberg. The Belgian study (BEL; PI D. Lambrechts) was funded by Nationaal Kankerplan. The BVU study (PI D.R.V. Edwards) was funded by Vanderbilt CTSA grant from the NIH/National Center for Advancing Translational Sciences (NCATS; ULTR000445). The CNIO Ovarian Cancer Study (CNI; PI J. Benitez) was supported by Instituto de Salud Carlos III (PI 12/01319), Ministerio de Economia y Competitividad (SAF2012). The Hawaii Ovarian Cancer Study (HAW; PI M.T. Goodman) was supported by the NIH (R01-CA58598, N01-CN55424 and N01-PC-67001). The Hannover-Jena Ovarian Cancer Study (HJO; PI T. D_ork) was supported by intramural funding through the Rudolf-Bartling Foundation. The Hormones and Ovarian Cancer Prediction study (HOP; PI K. Moysich) was supported by NCI: K07-CA80668; R01CA095023; P50-CA159981; R01-CA126841; US Army Medical Research andMateriel Command: DAMD17-021-0669; NIH/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056. The Women's Cancer Program (LAX; PI B.Y. Karlan) was supported by the American Cancer Society Early Detection Professorship (120950-SIOP-06-258-06-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. The Mayo Clinic Case-Only Ovarian Cancer Study (MAC; PI E.L. Goode) and the Mayo Clinic Ovarian Cancer CaseControl Study (MAY; PI E.L. Goode) were funded by the NIH (R01-CA122443, P30CA15083, P50-CA136393), Mayo Foundation, Minnesota Ovarian Cancer Alliance, Fred C. and Katherine B. Andersen Foundation, and Fraternal Order of Eagles. The MALOVA study (MAL; PI S.K. Kjaer) was funded by research grant R01-CA61107 from the NCI; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project. The North Carolina Ovarian Cancer Study (NCO; PI J.M. Schildkraut) was funded by the NIH (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666). The New England-based CaseControl Study of Ovarian Cancer (NEC; PI K.L. Terry) was supported by NIH grants R01 CA 054419-10 and P50 CA105009, and Department of Defense CDMRP grant W81XWH-10-1-0280. The University of Bergen, Haukeland University Hospital, Norway study (NOR; PI L. Bjorge) was funded by Helse Vest, The Norwegian Cancer Society, and The Research Council ofNorway. TheOregon study (ORE; PI T. Pejovic) was funded by the Sherie Hildreth Ovarian Cancer Research Fund and the OHSU Foundation. The Ovarian Cancer Prognosis and Lifestyle Study (OPL; PI P.M. Webb) was funded by National Health and Medical Research Council(NHMRC) of Australia (APP1025142 and APP1120431) and Brisbane Women's Club. The Danish Pelvic Mass Study (PVD; PI E. Hogdall) was funded by Herlev Hospitals Forskningsra~ d, Direktor Jacob Madsens og Hustru Olga Madsens fond, Arvid Nilssons fond, Gangsted fonden, Herlev Hospitals Forskningsra~ d, and Danish Cancer Society. The Royal Brisbane Hospital (RBH; PI G. Chenevix-Trench) study was funded by the National Health and Medical Research Council of Australia.The Scottish Randomised Trial in Ovarian Cancer study (SRO; PIs S. Kaye and P. Vasey) was funded by Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589). The Princess Margaret Cancer Centre study (UHN; PI T. May) was funded by Princess Margaret Cancer Centre Foundation-Bridge for the Cure. The Gynaecological Oncology Biobank at Westmead (WMH; PI A. deFazio) is a member of the Australasian Biospecimen NetworkOncology group, funded by the Australian National Health and Medical Research Council Enabling Grants IDs 310670 and 628903 and the Cancer Institute NSW Grant ID 12/RIG/1-17 and 15/RIG/1-16. OVCARE Gynecologic Tissue Bank and Outcomes Unit (VAN; PI D.G. Huntsman) study was funded by BC Cancer Foundation, VGH and UBC Hospital Foundation. Laboratory assays were funded by NHMRC Project Grant APP1158083 and Program Grant 1113867.AdeF was funded by the University of Sydney Cancer Research Fund and the Cancer Institute NSW through the Sydney West-Translational Cancer Research Centre. BYK is supported by American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. IO was supported by NCI CCSG award (P30-CA008748). GCT, SM, TOM, SLE, and PW are funded by NHMRC Fellowships. This project has also received support from the D. and J. Wilson Foundation to GCT.This study would not have been possible without the contributions of the following: Per Hall (COGS); Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer, and the staff of Mayo Clinic Genotyping Core Facility.The OncoArray collaboration arose, in part, through the efforts of the Genetic Associations and Mechanisms in Oncology (GAME-ON, http://epi.grants.cancer.gov/gameon/) consortium, which was a multiyear project to characterize SNP associations for common cancers and to understand theirmechanistic and functional consequences in disease development. We wish to pay tribute to the contribution of Professor Brian Henderson to the GAME-ON consortium.We are grateful to the family and friends of Kathryn Sladek Smith for their generous support for the OCAC through their donations to the Ovarian Cancer Research Fund. The authors wish to thank Margie Riggan for her tireless dedication to the OCAC through her excellent project and data management. We thank study participants, doctors, nurses, clinical and scientific collaborators, health care providers, and health information sources who have contributed to the following specific studies; the Australian Ovarian Cancer Study (AOCS) Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb) thank all the clinical and scientific collaborators (see http://www.aocstudy.org/) and the women for their contribution. The Belgian study (BEL) would like to thank Gilian Peuteman, Thomas Van Brussel, and Dominiek Smeets for technical assistance.The International Collaborative Ovarian Neoplasm study (ICON)7 trial team would like to thank theMedical Research Council (MRC) Clinical Trial Unit (CTU) at the University of London (UCL), the ICON7 Translational Research Sub-group, and the University of Leeds for their work on the coordination of samples and data from the ICON7 trial. The Mayo Clinic Ovarian Cancer Case-Control Study (MAY) thank C. Hilker, S. Windebank, and J. Vollenweider for iSelect genotyping. The Scottish Randomised Trial in Ovarian Cancer (SRO) thank all members of Scottish Gynaecological Clinical Trials group and SCOTROC1 investigators. The results published here are in part based upon data generated by TCGA Pilot Project established by the NCI and National Human Genome Research Institute. Information about TCGA can be found at http://cancergenome.nih.gov/.The Westmead Hospital Molecular Biology of Gynaecologic Disease (WMH) thanks the Gynaecological Oncology Biobank at Westmead.