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. 2018 Mar 6;168(5):326-334.
doi: 10.7326/M17-0101. Epub 2018 Jan 16.

White Blood Cell BRCA1 Promoter Methylation Status and Ovarian Cancer Risk

Per E Lønning  1 , Elisabet O Berge  1 , Merete Bjørnslett  2 , Laura Minsaas  1 , Ranjan Chrisanthar  1 , Hildegunn Høberg-Vetti  3 , Cécile Dulary  4 , Florence Busato  4 , Silje Bjørneklett  1 , Christine Eriksen  1 , Reidun Kopperud  3 , Ulrika Axcrona  5 , Ben Davidson  5 , Line Bjørge  1 , Gareth Evans  6 , Anthony Howell  7 , Helga B Salvesen  1 , Imre Janszky  8 , Kristian Hveem  8 , Pål R Romundstad  8 , Lars J Vatten  8 , Jörg Tost  4 , Anne Dørum  2 , Stian Knappskog  1
Affiliations

White Blood Cell BRCA1 Promoter Methylation Status and Ovarian Cancer Risk

Per E Lønning et al. Ann Intern Med. .

Abstract

Background: The role of normal tissue gene promoter methylation in cancer risk is poorly understood.

Objective: To assess associations between normal tissue BRCA1 methylation and ovarian cancer risk.

Design: 2 case-control (initial and validation) studies.

Setting: 2 hospitals in Norway (patients) and a population-based study (control participants).

Participants: 934 patients and 1698 control participants in the initial study; 607 patients and 1984 control participants in the validation study.

Measurements: 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).

Results: 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.

Limitations: Patients with ovarian cancer were recruited at the time of diagnosis in a hospital setting.

Conclusion: Constitutively normal tissue BRCA1 promoter methylation is positively associated with risk for HGSOC.

Primary funding source: Norwegian Cancer Society.

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