open access publication

Article, 2024

Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease

Npj Genomic Medicine, ISSN 2056-7944, Volume 9, 1, 10.1038/s41525-024-00395-y

Contributors

Ramachandran D. 0000-0001-8139-7799 [1] Tyrer J.P. 0000-0003-3724-4757 [2] Kommoss S. [3] deFazio A. 0000-0003-0057-4744 [4] [5] Riggan M.J. 0000-0002-3701-8031 [6] Webb P.M. 0000-0003-0733-5930 [7] Fasching P.A. 0000-0003-4885-8471 [8] Lambrechts D. 0000-0002-3429-302X [9] [10] Garcia M.J. 0000-0002-2236-9912 [11] Rodriguez-Antona C. 0000-0001-8750-7338 [12] [13] Goodman M.T. [14] Modugno F. 0000-0003-0637-1534 [15] [16] [17] Moysich K.B. [18] Karlan B.Y. 0000-0002-9451-2933 [19] Lester J. [19] Kjaer S.K. 0000-0002-8347-1398 [20] [21] Jensen A. 0000-0001-8124-4880 [20] Hogdall E. 0000-0003-4689-5658 [22] Goode E.L. 0000-0002-9094-8326 [23] Cliby W.A. [23] Kumar A. [23] Wang C. [23] Cunningham J.M. 0000-0002-8159-3025 [23] Winham S.J. 0000-0002-8492-9102 [23] Monteiro A.N.A. 0000-0002-8448-4801 [24] Schildkraut J.M. 0000-0002-0990-9339 [25] Cramer D.W. 0000-0002-8024-3066 [26] [27] Terry K.L. [26] [27] Titus L. [28] Bjorge L. [29] [30] Thomsen L.C.V. [29] [30] Pejovic T. [31] Hogdall C. 0000-0002-5959-8874 [21] McNeish I. 0000-0002-9387-7586 [32] [33] May T. [34] Huntsman D. [35] [36] Pfisterer J. [37] Canzler U. [38] [39] Park-Simon T.-W. [1] Schroder W. [40] Belau A. [41] Hanker L.C. [42] [43] Harter P. 0000-0002-9663-5005 [44] Sehouli J. 0000-0002-5963-6623 [45] Kimmig R. 0000-0003-1118-2199 [46] de Gregorio N. [47] Schmalfeldt B. [48] Baumann K. [49] [50] Hilpert F. [51] [52] Burges A. [53] Winterhoff B. [54] Schurmann P. [1] Speith L.-M. [1] Hillemanns P. 0000-0001-9829-3531 [1] Berchuck A. [6] Johnatty S.E. [7] Ramus S.J. 0000-0003-0005-7798 [55] [56] Chenevix-Trench G. 0000-0002-1878-2587 [7] Pharoah P.D.P. 0000-0001-8494-732X [2] [14] [57] Dork T. 0000-0002-9458-0282 (Corresponding author) [1] Heitz F. 0000-0002-2412-0352 (Corresponding author) [44] [45] [58] Bowtell D.D.L. [59] Fereday S. 0000-0002-8559-8579 [59] Traficante N. [59] Hung J.A. [7] Friedlander M. 0000-0003-3090-795X [56] Obermair A. [7] Grant P. [59] Beesley V. [7] Blomfield P. [7] Brand A. [5] Davis A. [7] Leung Y. [7] Nicklin J. [7] Quinn M. [7] Livingstone K. [7] O'Neill H. [7] Williams M. [7]

Affiliations

  1. [1] Hannover Medical School
    2. [NORA names: Germany; Europe, EU; OECD];
  2. [2] Department of Oncology
    3. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  3. [3] University Hospital Tübingen
    4. [NORA names: Germany; Europe, EU; OECD];
  4. [4] University of Sydney
    5. [NORA names: Australia; Oceania; OECD];
  5. [5] Westmead Hospital
    6. [NORA names: Australia; Oceania; OECD];

Abstract

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

Funders

  • Ovarian Cancer Research Fund
  • Helse Vest
  • Cancer Research Society
  • National Health & Medical Research Council of Australia
  • Kreftforeningen
  • Cancer Research UK
  • U.S. Department of Defense
  • United States/National Cancer Institute
  • Ministerio de Economía y Competitividad
  • Princess Margaret Cancer Centre Foundation-Bridge for the Cure
  • National Center for Advancing Translational Sciences
  • Wellcome Trust
  • VGH and UBC Hospital Foundation
  • Minnesota Ovarian Cancer Alliance
  • Canadian Institutes of Health Research
  • Cancer Councils of New South Wales
  • Instituto de Salud Carlos III
  • Brisbane Women’s Club
  • Imperial Experimental Cancer Research Centre
  • Seventh Framework Programme
  • BC Cancer Foundation
  • Peter MacCallum Foundation
  • National Cancer Institute
  • Fraternal Order of Eagles
  • Merck Pharmaceuticals
  • Canadian Cancer Society
  • Roche Pharma AG
  • Norges Forskningsråd
  • National Institutes of Health
  • Kræftens Bekæmpelse
  • American Cancer Society
  • National Health and Medical Research Council
  • Ovarian Cancer Australia
  • School of Dental Medicine, University of Pittsburgh
  • Medical Research and Materiel Command
  • Mayo Foundation for Medical Education and Research
  • Friedrich-Alexander-Universität Erlangen-Nürnberg

Data Provider: Elsevier

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