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, Page 19, 10.1038/s41525-024-00395-y

Contributors

Ramachandran, Dhanya 0000-0001-8139-7799 [1] Tyrer, Jonathan P 0000-0003-3724-4757 [2] Kommoss, Stefan [3] Defazio, Anna 0000-0003-0057-4744 [4] [5] [6] Riggan, Marjorie J [7] Webb, Penelope M 0000-0003-0733-5930 [8] Fasching, Peter A [9] [10] Lambrechts, Diether 0000-0002-3429-302X [11] [12] García, María J. [13] Rodríguez-Antona, Cristina 0000-0001-8750-7338 [14] [15] Goodman, Marc T 0000-0002-4839-3021 [16] Modugno, Francesmary- 0000-0003-0637-1534 [17] [18] Moysich, Kirsten B [19] Karlan, Beth R Young 0000-0002-9451-2933 [20] Lester, Jenny [20] Kjaer, Susanne Kriiger 0000-0002-8347-1398 [21] [22] [23] Jensen, Allan [21] Høgdall, Estrid Vilma Solyom 0000-0003-4689-5658 [22] Goode, Ellen L [24] Cliby, William A 0000-0002-7565-9884 [24] Kumar, Amanika 0000-0002-1470-1305 [24] Wang, Chen [24] Cunningham, Julie M 0000-0002-8159-3025 [24] Winham, Stacey J 0000-0002-8492-9102 [24] Monteiro, Alvaro N A 0000-0002-8448-4801 [25] Schildkraut, Joellen Martha [26] Cramer, Daniel William 0000-0002-8024-3066 [27] [28] Terry, Kathryn L. [27] [28] Titus, Linda J [29] Bjørge, Line 0000-0002-0240-2770 [30] [31] Thomsen, Liv Cecilie Vestrheim 0000-0002-6787-8518 [30] [31] Pejovic, Tanja B 0000-0001-8537-1086 [32] [33] Høgdall, Claus Kim 0000-0002-5959-8874 [22] [23] Mcneish, Iain A 0000-0002-9387-7586 [34] [35] May, Taymaa [36] Huntsman, David George [37] [38] Pfisterer, J For The Ago Organkommission Ovar [39] Canzler, Ulrich [40] [41] [42] Park-Simon, Tjoung-Won 0000-0002-2863-3040 [1] Schröder, Willibald [43] [44] Belau, Antje Kristina [45] [46] Hanker, Lars Christian 0000-0001-6697-018X [39] [47] Harter, Philipp 0000-0002-9663-5005 [48] Sehouli, Jalid [49] Kimmig, Rainer Klaus [50] [51] De Gregorio, Nikolaus [52] [53] Schmalfeldt, Barbara [54] Baumann, Klaus Heinrich 0000-0002-7998-0763 [55] [56] Hilpert, Felix [39] [57] Burges, Alexander [58] Winterhoff, Boris J N [59] Schürmann, Peter [1] Speith, Lisa-Marie [1] Hillemanns, Peter [1] Berchuck, Andrew 0000-0002-1940-1467 [7] Johnatty, Sharon E 0000-0002-7888-1966 [8] Ramus, Susan J 0000-0003-0005-7798 [60] Chenevix-Trench, Georgia- 0000-0002-1878-2587 [8] Pharoah, Paul David Peter 0000-0001-8494-732X [2] [16] Dörk, Thilo 0000-0002-9458-0282 (Corresponding author) [1] Heitz, Florian 0000-0002-2412-0352 (Corresponding author) [48] [49] [61]

Affiliations

  1. [1] Hannover Medical School
    2. [NORA names: Germany; Europe, EU; OECD];
  2. [2] University of Cambridge
    3. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  3. [3] Universitätsklinikum Tübingen
    4. [NORA names: Germany; Europe, EU; OECD];
  4. [4] The 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 × 10−8). 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.

Keywords

AGO-OVAR, DNA, DNA repair enzymes, MGMT, PP2A, PPP2R5C, adjustment, analysis, association, association analysis, cancer, cancer patients, carcinoma, debulking surgery, disease, enzyme, gene-based analysis, genes, genome-wide association analysis, heritable variation, high-grade serous carcinoma, levels, loci, mRNA levels, methylation, ovarian cancer, ovarian cancer patients, ovarian tumors, patients, primary debulking surgery, primary surgery, progression-free survival, repair enzymes, resection, resection status, residual disease, results, serous carcinoma, stage, stage adjustment, status, study, subunit, suppressor, surgery, survival, transcript levels, transcription, tumor, tumor suppressor, variants, variation

Funders

  • Andersen (United States)
  • Congressionally Directed Medical Research Programs
  • Ministry of Economy, Industry and Competitiveness
  • Roche (Switzerland)
  • Instituto de Salud Carlos III
  • National Institutes of Health
  • Deutsche Forschungsgemeinschaft
  • The Research Council of Norway
  • Canadian Cancer Society
  • Ovarian Cancer Research Alliance
  • American Cancer Society
  • Danish Cancer Society
  • National Center for Advancing Translational Sciences
  • Moffitt Cancer Center
  • National Human Genome Research Institute
  • National Cancer Institute
  • Department of Health and Social Care
  • National Health and Medical Research Council
  • Cancer Australia
  • Cancer Institute of New South Wales
  • United States Army Medical Research and Development Command
  • Mayo Clinic
  • Cancer Research Society
  • Wellcome Trust
  • Canadian Institutes of Health Research
  • European Commission
  • Cancer Research UK
  • Norwegian Cancer Society

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