The genetic basis for cancer is firmly established, and increasing evidence indicates that other factors, such as aberrant gene regulation, can also play a role in tumorigenesis. Now the role in carcinogenesis of an important gene transcription regulator, DNA methylation, has become a focus of attention.1
Researchers at Haukeland University Hospital in Bergen, Norway, recently assessed the relationship between normal tissue BRCA1 methylation and ovarian cancer risk.2 The results were published in the Annals of Internal Medicine.
Although women with mutations in BRCA1 and BRCA2 genes are known to be at high risk for breast and epithelial ovarian cancers, especially high-grade serous ovarian cancer (HGSOC), the association between BRCA1 methylation in white blood cells (WBCs) and the risk of breast and ovarian cancer has not been clearly defined.
“We found a positive association between mosaic normal tissue (WBC) BRCA1 methylation status and the risk for ovarian cancer, particularly HGSOC,” wrote the authors, who were led by Per Eystein Lønning, MD, PhD. “Also, WBC 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 HGSOC later in life.”
In an initial study, the investigators evaluated WBC DNA before chemotherapy in 934 patients with epithelial ovarian cancer and in 1,698 women without cancer, and validated the results with a second study with 607 ovarian cancer patients and 1984 healthy controls. WBC BRCA1 promoter methylation was determined, and the percentage of methylation-positive samples was compared between groups. A subgroup with HGSOC was also evaluated.
The researchers reported BRCA1 methylation among 6.4% of patients diagnosed with ovarian cancer compared with 4.2% among controls (odds ratio [OR], 1.83). Importantly, elevated BRCA1 methylation was confined to patients diagnosed with HGSOC tumors, the most aggressive variant of ovarian cancer.
Among patients with HGSOC tumors, methylation was detected among 9.6% of individuals, corresponding to an almost 3-fold increase in risk for individuals harboring methylation (age-adjusted OR, 2.91). Methylation for nonserous and low-grade serous ovarian cancer was similar to controls (5.1% and 4.0%, respectively). The results were similar in the validation study.
White blood cell methylation status was determined in 611 newborn girls and 292 healthy women aged 20-25 years to assess change of BRCA1 methylation over time. BRCA1 methylation status was highest in newborns vs young women (7.0% and 4.1%, respectively). Positive promoter methylation status generally decreased with increasing age in healthy women and patients with cancer.
To explore the relationship between WBC BRCA1 methylation and BRCA1/2 germline mutation, BRCA1 methylation status was determined in 251 women with ovarian cancer and germline BRCA1 mutations. One hundred had BRCA2 mutations, and 15 had familial ovarian cancer with negative results on BRCA1/2 mutation testing. BRCA1 methylation status was determined in 276 of 351 patients, including 6 of 72 women carrying BRCA2 mutations but only 3 of 204 women with BRCA1 mutations.
The authors noted that the study’s limitations included the retrospective design, and the influences of different diseases on WBC methylation status and of unmeasured confounding on associations.
“We found a positive association between WBC BRCA1 promoter methylation and ovarian cancer risk in a large case-control study, and confirmed the main findings in a similarly designed validation study,” the investigators concluded. “In both studies, the positive association was limited to the subgroup of patients with HGSOC, which is consistent with findings from earlier studies of women with BRCA1 germline mutations.”
To read more about this study, click here.
- Klutstein M, et al. Cancer Res. 2016;76(12):3446-3450.
- Lønning PE, et al. Ann Intern Med. 2018. DOI: 10.7326/M17-0101.