White blood cell BRCA1 methylation linked to elevated ovarian cancer risk
medwireNews: Individuals with high-grade serous ovarian cancer (HGSOC) are more than twice as likely as those without cancer to have white blood cell (WBC) BRCA1 promoter methylation, study findings indicate.
The researchers also found that WBC BRCA1 methylation is highest in newborns and decreases with age, suggesting that “normal tissue BRCA1 methylation is probably an embryonic event that might influence the risk for HGSOC later in life,” they write.
Per Lønning (Haukeland University Hospital, Bergen, Norway) and colleagues report that WBC BRCA1 promoter methylation was significantly more common in 934 patients with ovarian cancer than in 1698 population-based control participants, at 6.4% versus 4.2%, giving an age-adjusted odds ratio (OR) of 1.83.
However, when they grouped the patients according to cancer grade, they found that methylation levels were only significantly elevated in those with HGSOC, at 9.6% (OR=2.91) and not in those with nonserous and low-grade serous ovarian cancer, at 5.1% and 4.0%, respectively.
Furthermore, the findings were replicated in a validation study of 607 patients and 1984 controls. In this case 6.1% of the patients and 4.3% of the controls had positive WBC BRCA1 methylation status, but only patients with HGSOC had a significantly higher level of methylation, at 9.1%, than controls (OR=2.22).
Lønning et al point out that their results were not influenced by tumor burden, previous treatment for breast cancer, storage time, or WBC subfractions.
The team also found that among patients with normal tissue samples available for analysis, 13 (54.2%) of 24 harboring WBC BRCA1 methylation also had BRCA1 methylation in non-WBC tissue, compared with none of 22 without WBC BRCA1 methylation.
In addition, ovarian cancer tissue methylation was present in 18 (62.1%) of 29 patients with WBC BRCA1 methylation but only seven (12.1%) of 58 without it.
This “supports the hypothesis that many of these cancer cases may have originated from methylated cells in ovarian tissue,” the authors write in the Annals of Internal Medicine.
A separate analysis of cord blood from 611 newborn girls and blood from 292 healthy women aged 20–25 years showed that WBC BRCA1 methylation decreased with age from 7.0% in newborns to 4.1% in young women. Decreases with age were also seen among the patients with ovarian cancer and the healthy controls.
“This and previous studies make it clear that BRCA1 constitutional methylation is strongly associated with the same tumor types as those with mutation of the gene,” writes Alexander Dobrovic, from the University of Melbourne, in Victoria, Australia, in an accompanying editorial.
However, he adds that questions remain over why disease develops in only some of the women with constitutional methylation. These include whether the risk is “stochastically or environmentally driven” and what causes constitutional BRCA1 methylation?
“The answers to these questions may have important implications for predicting and preventing these types of cancer in the future,” Dobrovic concludes.
By Laura Cowen
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