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Normal tissue BRCA1 linked to high-grade ovarian cancer risk

Patients with normal tissue BRCA1 methylation have a higher risk for ovarian cancer, especially high-grade serous ovarian cancer, according to research published in Annals of Internal Medicine.

Furthermore, the researchers found that normal tissue BRCA1 methylation may occur as a prenatal event and possibly influence cancer risk later in life.

“The role of normal tissue gene promoter methylation in cancer risk is poorly understood,” Per E. Lønning, MD, PhD, from the University of Bergen and Haukeland University, Norway, and colleagues wrote.

Lønning and colleagues conducted two case-control studies to investigate the effect of normal tissue BRCA1 methylation on ovarian cancer risk. The researchers included 934 patients and 1,698 control patients in the initial study and 607 patients and 1,984 control patients in the validation study.

Prior to chemotherapy, all patients underwent blood sampling. The researchers used methylation-specific quantitative polymerase chain reaction to determine the white blood cell BRCA1 promoter methylation. Then, they compared the percentage of methylation-positive samples among patients with ovarian cancer and population control participants.

The initial study revealed that patients with ovarian cancer more commonly had BRCA1 methylation, compared with control participants (6.4% vs. 4.2%; age-adjusted OR = 1.83; 95% CI, 1.27-2.63). Only patients with high-grade serous ovarian cancer had elevated methylation (9.6%; OR = 2.91; 95% CI, 1.85-4.56). Methylation frequency was 5.1% for patients with nonserous ovarian cancer and 4% for those with low-grade serous ovarian cancer.

The validation study showed similar results, with methylation detected in 9.1% of participants with high-grade serous ovarian cancer vs. 4.3% of control participants (OR = 2.22; 95% CI, 1.4-3.52). Additionally, a methylation-positive status was observed in 4.1% of patients with nonserous ovarian cancer and 2.7% of those with low-grade serous ovarian cancer.

Tumor burden, storage time and white blood cell subfractions did not impact these findings.

An additional analysis indicated that BRCA1 methylation was observed in 4.1% (95% CI, 1.8%-6.4%) of young women and 7% (95% CI, 5.0%-9.1%) of newborns.

“We found a positive association between mosaic normal tissue [white blood cell] BRCA1 methylation status and the risk for ovarian cancer, particularly [high-grade serous ovarian cancer],” Lønning and colleagues concluded. “Also, [white blood cell] BRCA1 methylation was detected in newborns and among women of all ages. Taken together, these observations indicate that normal tissue BRCA1 methylation is probably an embryonic event that might influence the risk for [high-grade serous ovarian cancer] later in life.”

In an accompanying editorial, Alexander Dobrovic, PhD, from the Olivia Newton-John Cancer Research Institute, Australia, wrote that the findings by Lønning and colleagues add to the evidence making it apparent that there is a strong association between BRCA1 methylation and the same tumor types as those with mutation of the gene.

“Although it is clear that [white blood cell] BRCA1 methylation is associated with an elevated risk for breast or ovarian cancer, the disease will develop in only some of the otherwise healthy women with constitutional methylation,” he wrote. “Is this risk stochastically or environmentally driven? What is the cause of constitutional BRCA1 methylation? The answers to these questions may have important implications for predicting and preventing these types of cancer in the future.” – by Alaina Tedesco

Disclosure: Lønning and Dobrovic report no relevant financial disclosures. Please see study for all other authors’ relevant financial disclosures.