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

Ramachandran D, Tyrer JP, Kommoss S, DeFazio A, Riggan MJ, Webb PM, Fasching P, Lambrechts D, García MJ, Rodríguez-Antona C, Goodman MT, Modugno F, Moysich KB, Karlan BY, Lester J, Kjaer SK, Jensen A, Høgdall E, Goode EL, Cliby WA, Kumar A, Wang C, Cunningham JM, Winham SJ, Monteiro AN, Schildkraut JM, Cramer DW, Terry KL, Titus L, Bjorge L, Thomsen LCV, Pejovic T, Høgdall CK, McNeish IA, May T, Huntsman DG, Pfisterer J, Canzler U, Park-Simon TW, Schröder W, Belau A, Hanker L, Harter P, Sehouli J, Kimmig R, de Gregorio N, Schmalfeldt B, Baumann K, Hilpert F, Burges A, Winterhoff B, Schürmann P, Speith LM, Hillemanns P, Berchuck A, Johnatty SE, Ramus SJ, Chenevix-Trench G, Pharoah PD, Dörk T, Heitz F, Bowtell D, Fereday S, Traficante N, Hung J, Friedlander M, Obermair A, Grant P, Beesley V, Blomfield P, Brand A, Davis A, Leung Y, Nicklin J, Quinn M, Livingstone K, O’Neill H, Williams M (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 9

Article Number: 19

Journal Issue: 1

DOI: 10.1038/s41525-024-00395-y

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.

Authors with CRIS profile

Involved external institutions

Danish Cancer Society Research Center Denmark (DK) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) Gentofte Hospital Denmark (DK) University Health Network (UHN) Canada (CA) Mayo Clinic United States (USA) (US) University of British Columbia Canada (CA) Brigham and Women's Hospital (BWH) United States (USA) (US) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Klinikverbund Bremen (Gesundheit Nord) Germany (DE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Cambridge United Kingdom (GB) Kliniken Essen-Mitte Germany (DE) Peter MacCallum Cancer Centre Australia (AU) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Universitätsklinikum Essen Germany (DE) Universitätsklinikum Ulm Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) University of Pittsburgh United States (USA) (US) University of California Los Angeles (UCLA) United States (USA) (US) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Klinikum der Universität München Germany (DE) University of New South Wales (UNSW) Australia (AU) Universidad Rey Juan Carlos Spain (ES) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Emory University United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) Dartmouth Cancer Center United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) Medford Women’s Clinic United States (USA) (US) Westmead Hospital Australia (AU) Rigshospitalet Denmark (DK) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) University of Minnesota (UMN) United States (USA) (US) University of Sydney (USYD) Australia (AU) Duke University Medical Center United States (USA) (US) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) Universitätsklinikum Tübingen Germany (DE)

How to cite

APA:

Ramachandran, D., Tyrer, J.P., Kommoss, S., DeFazio, A., Riggan, M.J., Webb, P.M.,... Williams, M. (2024). Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease. npj Genomic Medicine, 9(1). https://doi.org/10.1038/s41525-024-00395-y

MLA:

Ramachandran, Dhanya, et al. "Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease." npj Genomic Medicine 9.1 (2024).

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