Per E. Lønning, MD, PhD; Elisabet O. Berge, PhD; Merete Bjørnslett, PhD; Laura Minsaas, PhD; Ranjan Chrisanthar, PhD; Hildegunn Høberg-Vetti, MD; Cécile Dulary, MSc; Florence Busato, MSc; Silje Bjørneklett, MSc; Christine Eriksen, MSc; Reidun Kopperud, PhD; Ulrika Axcrona, MD; Ben Davidson, MD, PhD; Line Bjørge, MD, PhD; Gareth Evans, MD, PhD; Anthony Howell, MD, PhD; Helga B. Salvesen, MD, PhD †; Imre Janszky, MD, PhD; Kristian Hveem, MD, PhD; Pål R. Romundstad, PhD; Lars J. Vatten, MD, PhD; Jörg Tost, PhD; Anne Dørum, MD, PhD; Stian Knappskog, PhD
Note: The corresponding authors had full access to all data during the study and had the final responsibility for submitting the manuscript.
Acknowledgment: The authors thank everyone who donated blood samples used in the present study. The control samples (from healthy donors) were obtained from the Norwegian CONOR biobanks. Most laboratory analyses were performed at the Mohn Cancer Research Laboratory in Bergen, Norway. They also authors thank Deepak B. Poduval and Zuzana Sichmanova for informatics assistance.
Financial Support: By the Norwegian Cancer Society, Norwegian Health West (Helse Vest; regional funding for medical research), Norwegian Research Council, and Bergen Research Foundation. Dr. Evans is supported by the National Institute for Health Research Manchester Biomedical Research Centre.
Disclosures: Dr. Evans reports personal fees from AstraZeneca outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-0101.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Romundstad (e-mail, firstname.lastname@example.org).
Requests for Single Reprints: Per E. Lønning, MD, PhD, Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway; e-mail, email@example.com.
Current Author Addresses: Drs. Lønning, Berge, Minsaas, Chrisanthar and Knappskog; Ms. Bjørneklett; and Ms. Eriksen: Section of Oncology, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway and Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway.
Dr. Bjørnslett: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, N-0316 Oslo, Norway.
Drs. Axcrona, and Davidson: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Department of Pathology, Oslo University Hospital, Ullernchausseen 70 Radiumhospitalet, Box 4950 Nydalen, N-0424 Oslo, Norway.
Dr. Høberg-Vetti: Department of Molecular Medicine and Medical Genetics, Haukeland University Hospital, N-5021 Bergen, Norway.
Ms. Dulary, Ms. Busato, and Dr. Tost: Laboratory for Epigenetics and Environment, Centre National de la Recherche en Génomique Humaine, CEA–Institut de Biologie Francois Jacob Batiment G2, 2 rue Gaston Crémieux, CP 5721, 91057 Evry Cedex, France.
Drs. Kopperud and Bjørge: Department of Clinical Science, University of Bergen, Centre for Cancer Biomarkers, University of Bergen, Department of Obstetrics and Gynecology, Haukeland University Hospital, N-5021 Bergen, Norway.
Dr. Evans: Department of Genomic Medicine, University of Manchester and Division of Evolution and Genomic Science, St Mary's Hospital, Manchester M13 9WL, United Kingdom.
Dr. Howell: Institute of Cancer Sciences, University of Manchester and Breast Cancer Now Unit, Manchester Cancer Research Centre, The Christie NHS Foundation Trust, 555 Wilmslow Road, Manchester M20 4GJ, United Kingdom.
Drs. Janszky, Romundstad, and Vatten: Department of Public Health, Norwegian University of Science and Technology, Boks 8905, N-7491 Tondheim, Norway.
Dr. Hveem: HUNT Biobank, K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology (NTNU) Forskningsvegen 2, N-7600 Levanger, Norway.
Dr. Dørum: Department of Gynecological Oncology, Oslo University Hospital, Norwegian Radium Hospital, N-0316 Oslo, Norway.
Author Contributions: Conception and design: P.E. Lønning, E.O. Berge, P.R. Romundstad, L.J. Vatten, S. Knappskog.
Analysis and interpretation of the data: P.E. Lønning, E.O. Berge, M. Bjørnslett, L. Minsaas, R. Chrisanthar, F. Busato, S. Bjørneklett, C. Eriksen, D.G. Evans, A. Howell, I. Janszky, P.R. Romundstad, L.J. Vatten, J. Tost, A. Dørum, S. Knappskog.
Drafting of the article: P.E. Lønning, E.O. Berge, M. Bjørnslett, L. Bjørge, D.G. Evans, A. Howell, L.J. Vatten, S. Knappskog.
Critical revision for important intellectual content: P.E. Lønning, E.O. Berge, D.G. Evans, A. Howell, I. Janszky, P.R. Romundstad, L.J. Vatten, A. Dørum, S. Knappskog.
Final approval of the article: P.E. Lønning, E.O. Berge, M. Bjørnslett, L. Minsaas, R. Chrisanthar, H. Høberg-Vetti, C. Dulary, F. Busato, S. Bjørneklett, C. Eriksen, R. Kopperud, U. Axcrona, B. Davidson, L. Bjørge, D.G. Evans, A. Howell, H.B. Salvesen, I. Janszky, K. Hveem, P.R. Romundstad, L.J. Vatten, J. Tost, A. Dørum, S. Knappskog.
Provision of study materials or patients: M. Bjørnslett, H. Høberg-Vetti, B. Davidson, L. Bjørge, D.G. Evans, A. Howell, H.B. Salvesen, K. Hveem, P.R. Romundstad; A. Dørum.
Statistical expertise: P.E. Lønning, E.O. Berge, I. Janszky, P.R. Romundstad, L.J. Vatten, S. Knappskog.
Obtaining of funding: P.E. Lønning, S. Knappskog.
Administrative, technical, or logistic support: P.E. Lønning, E.O. Berge, M. Bjørnslett, L. Minsaas, R. Chrisanthar, C. Dulary, S. Bjørneklett, C. Eriksen, R. Kopperud, L. Bjørge, D.G. Evans, K. Hveem, J. Tost, S. Knappskog.
Collection and assembly of data: P.E. Lønning, E.O. Berge, M. Bjørnslett, L. Minsaas, S. Bjørneklett, C. Eriksen, R. Kopperud, U. Axcrona, B. Davidson, L. Bjørge, D.G. Evans, K. Hveem, P.R. Romundstad, L.J. Vatten, A. Dørum, S. Knappskog.
The role of normal tissue gene promoter methylation in cancer risk is poorly understood.
To assess associations between normal tissue BRCA1 methylation and ovarian cancer risk.
2 case–control (initial and validation) studies.
2 hospitals in Norway (patients) and a population-based study (control participants).
934 patients and 1698 control participants in the initial study; 607 patients and 1984 control participants in the validation study.
All patients had their blood sampled before chemotherapy. White blood cell (WBC) BRCA1 promoter methylation was determined by using methylation-specific quantitative polymerase chain reaction, and the percentage of methylation-positive samples was compared between population control participants and patients with ovarian cancer, including the subgroup with high-grade serous ovarian cancer (HGSOC).
In the initial study, BRCA1 methylation was more frequent in patients with ovarian cancer than control participants (6.4% vs. 4.2%; age-adjusted odds ratio [OR], 1.83 [95% CI, 1.27 to 2.63]). Elevated methylation, however, was restricted to patients with HGSOC (9.6%; OR, 2.91 [CI, 1.85 to 4.56]), in contrast to 5.1% and 4.0% of patients with nonserous and low-grade serous ovarian cancer (LGSOC), respectively. These findings were replicated in the validation study (methylation-positive status in 9.1% of patients with HGSOC vs. 4.3% of control participants—OR, 2.22 [CI 1.40 to 3.52]—4.1% of patients with nonserous ovarian cancer, and 2.7% of those with LGSOC). The results were not influenced by tumor burden, storage time, or WBC subfractions. In separate analyses of young women and newborns, BRCA1 methylation was detected in 4.1% (CI, 1.8% to 6.4%) and 7.0% (CI, 5.0% to 9.1%), respectively.
Patients with ovarian cancer were recruited at the time of diagnosis in a hospital setting.
Constitutively normal tissue BRCA1 promoter methylation is positively associated with risk for HGSOC.
Norwegian Cancer Society.
Lønning PE, Berge EO, Bjørnslett M, Minsaas L, Chrisanthar R, Høberg-Vetti H, et al. White Blood Cell BRCA1 Promoter Methylation Status and Ovarian Cancer Risk. Ann Intern Med. 2018;168:326–334. doi: 10.7326/M17-0101
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Published: Ann Intern Med. 2018;168(5):326-334.
Published at www.annals.org on 16 January 2018
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