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

Dhanya Ramachandran; Jonathan P Tyrer; Stefan Kommoss; Anna DeFazio; Marjorie J Riggan; AOCS Group; Penelope M Webb; Peter A Fasching; Diether Lambrechts; María J García; Cristina Rodríguez-Antona; Marc T Goodman; Francesmary Modugno; Kirsten B Moysich; Beth Y Karlan; Jenny Lester; Susanne K Kjaer; Allan Jensen; Estrid Høgdall; Ellen L Goode; William A Cliby; Amanika Kumar; Chen Wang; Julie M Cunningham; Stacey J Winham; Alvaro N Monteiro; Joellen M Schildkraut; Daniel W Cramer; Kathryn L Terry; Linda Titus; Line Bjorge; Liv Cecilie Vestrheim Thomsen; OPAL Study Group; Tanja Pejovic; Claus K Høgdall; Iain A McNeish; Taymaa May; David G Huntsman; Jacobus Pfisterer; Ulrich Canzler; Tjoung-Won Park-Simon; Willibald Schröder; Antje Belau; Lars Hanker; Philipp Harter; Jalid Sehouli; Rainer Kimmig; Nikolaus de Gregorio; Barbara Schmalfeldt; Klaus Baumann; Felix Hilpert; Alexander Burges; Boris Winterhoff; Peter Schürmann; Lisa-Marie Speith; Peter Hillemanns; Andrew Berchuck; Sharon E Johnatty; Susan J Ramus; Georgia Chenevix-Trench; Paul D P Pharoah; Thilo Dörk; Florian Heitz

doi:10.1038/s41525-024-00395-y

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

NPJ Genom Med. 2024 Mar 5;9(1):19. doi: 10.1038/s41525-024-00395-y.

Authors

Dhanya Ramachandran¹, Jonathan P Tyrer², Stefan Kommoss³, Anna DeFazio^{4

5

6

7}, Marjorie J Riggan⁸; AOCS Group; Penelope M Webb⁹, Peter A Fasching¹⁰, Diether Lambrechts^{11

12}, María J García¹³, Cristina Rodríguez-Antona^{14

15}, Marc T Goodman¹⁶, Francesmary Modugno^{17

18

19}, Kirsten B Moysich²⁰, Beth Y Karlan²¹, Jenny Lester²¹, Susanne K Kjaer^{22

23}, Allan Jensen²², Estrid Høgdall²⁴, Ellen L Goode²⁵, William A Cliby²⁶, Amanika Kumar²⁶, Chen Wang²⁷, Julie M Cunningham²⁸, Stacey J Winham²⁷, Alvaro N Monteiro²⁹, Joellen M Schildkraut³⁰, Daniel W Cramer^{31

32}, Kathryn L Terry^{31

32}, Linda Titus³³, Line Bjorge^{34

35}, Liv Cecilie Vestrheim Thomsen^{34

35}; OPAL Study Group; Tanja Pejovic^{36

37}, Claus K Høgdall²³, Iain A McNeish^{38

39}, Taymaa May⁴⁰, David G Huntsman^{41

42}, Jacobus Pfisterer⁴³, Ulrich Canzler^{44

45}, Tjoung-Won Park-Simon¹, Willibald Schröder^{46

47}, Antje Belau^{48

49}, Lars Hanker^{50

51}, Philipp Harter⁵², Jalid Sehouli⁵³, Rainer Kimmig⁵⁴, Nikolaus de Gregorio^{55

56}, Barbara Schmalfeldt⁵⁷, Klaus Baumann^{58

59}, Felix Hilpert^{60

61}, Alexander Burges⁶², Boris Winterhoff⁶³, Peter Schürmann¹, Lisa-Marie Speith¹, Peter Hillemanns¹, Andrew Berchuck⁸, Sharon E Johnatty⁶⁴, Susan J Ramus^{65

66}, Georgia Chenevix-Trench⁶⁴, Paul D P Pharoah^{2

67

68}, Thilo Dörk⁶⁹, Florian Heitz^{70

71

72}

Collaborators

David Bowtell, Sian Fereday, Nadia Traficante, Jillian Hung, Michael Friedlander, Andreas Obermair, Peter Grant, Vanessa Beesley, Penelope Blomfield, Alison Brand, Alison Davis, Yee Leung, James Nicklin, Michael Quinn, Karen Livingstone, Helen O'Neill, Merran Williams

Affiliations

¹ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³ Department of Women's Health, Tuebingen University Hospital, Tuebingen, Germany.
⁴ Centre for Cancer Research, The Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
⁵ Discipline of Obstetrics and Gynaecology, The University of Sydney, Sydney, NSW, Australia.
⁶ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
⁷ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia.
⁸ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
⁹ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹⁰ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
¹¹ Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
¹² VIB Center for Cancer Biology, VIB, Leuven, Belgium.
¹³ Biochemistry and Molecular Biology area, Department of Basic Health Sciences, Faculty of Health Sciences, Rey Juan Carlos University, Madrid, Spain.
¹⁴ Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
¹⁵ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
¹⁶ Cancer Prevention and Control Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁷ Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
¹⁸ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁹ Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
²⁰ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
²¹ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
²² Department of Virus, Lifestyle and Genes, Danish Cancer Institute, Copenhagen, Denmark.
²³ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
²⁴ Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
²⁵ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
²⁶ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo Clinic, Rochester, MN, USA.
²⁷ Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA.
²⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁹ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
³⁰ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
³¹ Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gyneclogy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³³ Norris Cotton Cancer Center, Lebanon, NH, USA.
³⁴ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
³⁵ Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
³⁶ Department of ObGyn, Providence Medical Center, Medford, OR, USA.
³⁷ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
³⁸ Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery & Cancer, Imperial College London, London, UK.
³⁹ Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
⁴⁰ Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada.
⁴¹ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
⁴² Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
⁴³ Gynecologic Oncology Center, Kiel, Germany.
⁴⁴ University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁴⁵ National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.
⁴⁶ Klinikum Bremen-Mitte, Bremen, Germany.
⁴⁷ Gynaekologicum Bremen, Bremen, Germany.
⁴⁸ University Hospital Greifswald, Greifswald, Germany.
⁴⁹ Frauenarztpraxis Belau, Greifswald, Germany.
⁵⁰ University Hospital Frankfurt, Frankfurt, Germany.
⁵¹ University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
⁵² Department of Gynecology and Gynecologic Oncology, Evangelische Kliniken Essen-Mitte (KEM), Essen, Germany.
⁵³ Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
⁵⁴ University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁵⁵ University Hospital Ulm, Ulm, Germany.
⁵⁶ SLK-Kliniken Heilbronn, Klinikum am Gesundbrunnen, Heilbronn, Germany.
⁵⁷ University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵⁸ University Hospital Gießen and Marburg, Site Marburg, Marburg, Germany.
⁵⁹ Klinikum Ludwigshafen, Ludwigshafen, Germany.
⁶⁰ University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
⁶¹ Krankenhaus Jerusalem, Mammazentrum Hamburg, Hamburg, Germany.
⁶² University Hospital LMU Munich, Munich, Germany.
⁶³ Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN, USA.
⁶⁴ Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁶⁵ School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, NSW, Australia.
⁶⁶ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, NSW, Australia.
⁶⁷ Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, CA, USA.
⁶⁸ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶⁹ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany. [email protected].
⁷⁰ Department of Gynecology and Gynecologic Oncology, Evangelische Kliniken Essen-Mitte (KEM), Essen, Germany. [email protected].
⁷¹ Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany. [email protected].
⁷² Department of Gynecology and Gynecological Oncology, HSK, Dr. Horst-Schmidt Klinik, Wiesbaden, Wiesbaden, Germany. [email protected].

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.

Abstract

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