Normal tissue BRCA1 methylation associated with risk for high-grade ovarian cancer

1. BRCA1 promoter methylation in normal white blood cells (WBCs) was linked to risk for high-grade serous ovarian cancer (HGSOC).

2. BRCA1 methylation was detected in women of all ages, including newborns, suggesting that BRCA1 methylation happens at an embryonic stage.

Evidence Rating Level: 3 (Average)    

Study Rundown: Females with BRCA1 mutations in their germline have a high risk of HGSOC.  However, BRCA1 methylation in normal tissues has also been detected in some families who are at high risk of breast cancer but do not have BRCA1 mutations in their germline.  The authors of this case-control study aimed to evaluate possible links between BRCA1 methylation in normal tissue and risk for ovarian cancer.  Researchers examined the WBCs of 934 patients and 1 698 healthy controls using methylation-specific quantitative polymerase chain reaction (qPCR).  The authors found that BRCA1 promoter methylation in normal tissue had a positive association with risk for HGSOC.  Results were confirmed through a validation study.  The authors detected BRCA1 methylation in women of all ages, including newborns.  This suggests that BRCA1 methylation likely happens at an embryonic stage and may affect future risk of HGSOC.

A strength of this study is that its conduction was consistent with the STREGA (Strengthening the Reporting of Genetic Association Studies) and GRIPS (Strengthening the Reporting of Genetic Risk Prediction Studies) statements.  A limitation of the study is that due to the difficult logistics of a prospective study design, a retrospective one was used: blood samples were collected from recruited ovarian cancer patients at the time of their diagnosis.

Click to read the study in the Annals of Internal Medicine

Click to read an accompanying editorial in Annals of Internal Medicine

Relevant Reading: LINE1 and Alu repetitive element DNA methylation in tumors and white blood cells from epithelial ovarian cancer patients

In-Depth [case-control study]: Using methylation-specific qPCR, the authors compared the BRCA1 promoter methylation status in the WBCs of 934 patients with those of 1 698 healthy controls in a preliminary study.  The authors conducted a similar analysis of 607 patients and 1 984 healthy controls in a validation study.  The patients were selected from two hospitals in Norway, and all blood samples were taken before the patients underwent chemotherapy.  Researchers found that BRCA1 methylation was present more often in ovarian cancer patients (6.4%) than healthy controls (4.2%).  Elevated methylation was limited to HGSOC patients (9.6%) compared to patients with nonserous (5.1%) and low-grade serous (4.0%) ovarian cancer.  The validation study produced similar results for HGSOC patients (9.1%), healthy controls (4.3%), nonserous ovarian cancer (4.1%), and low-grade serous ovarian cancer (2.7%).  WBC subfractions, tumor burden, and sample storage time did not affect the results.  WBC BRCA1 methylation was found most frequently in newborns (7.0% compared to 4.1% in young women).

Image: PD

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