In a case-control study within the U.S. Women’s Health Initiative (WHI) study population reported in JAMA Oncology, Lønning et al found that BRCA1 promoter methylation identified in white blood cells was associated with increased risks of incident triple-negative breast cancer and high-grade serous ovarian cancer.
As stated by the investigators, “About 25% of all triple-negative breast cancers and 10% to 20% of high-grade serous ovarian cancers harbor BRCA1 promoter methylation. While constitutional BRCA1 promoter methylation has been observed in normal tissues of some individuals, the potential role of normal tissue methylation as a risk factor for incident triple-negative breast cancer or high-grade serous ovarian cancer is unknown.”
Study Details
The analysis included women with no diagnosis of breast or ovarian cancer prior to entry in the WHI study. A total of 637 women developing incident triple-negative breast cancer and 511 developing incident high-grade serous ovarian cancer were matched with 1,841 and 2,982 cancer-free controls, respectively. Blood samples taken at entry into the WHI study were analyzed for BRCA1 promoter methylation by massive parallel sequencing at Mohn Cancer Research Laboratory in Bergen, Norway, between 2019 and 2022. Overall, 93% of cases and controls were White.
Key Findings
Methylated BRCA1 alleles were identified in 194 controls (5.5%), compared with 79 triple-negative breast cancer cases (12.4%) and 48 high-grade serous ovarian cancer cases (9.4%). Median times to diagnosis from entry into the WHI study were 9 years for triple-negative breast cancer and 10 years for high-grade serous ovarian cancer.
On multivariate analysis, methylation was associated with a significantly increased risk of incident triple-negative breast cancer (hazard ratio [HR] = 2.35, 95% confidence interval [CI] = 1.70–3.23, P < .001) and incident high-grade serous ovarian cancer (HR = 1.93, 95% CI = 1.36–2.73, P < .001).
Hazard ratios for triple-negative breast cancer were 1.83 (95% CI = 0.92–3.64, P = .08) for cases diagnosed at ≤ 5 years and 2.52 (95% CI = 1.75–3.63, P < .001) for cases diagnosed at > 5 years after blood sampling. The corresponding hazard ratios for high-grade serous ovarian cancer were 2.28 (95% CI = 1.13–4.59, P = .02) and 1.82 (95% CI = 1.22–2.72, P = .003).
BRCA1 methylation was not found to be haplotype-specific across individuals, suggesting that methylation was not associated with a cis-acting factor (factor located on the same allele as the methylation). Within individuals, BRCA1 methylation was observed on the same allele, indicating that methylation may have occurred as a single early event followed by clonal expansion.
No significant associations were observed between BRCA1 methylation and germline BRCA1 or BRCA2 pathogenic variant status or germline status of 26 additional cancer risk genes analyzed.
The investigators concluded, “The results of this case-control suggest that constitutional normal tissue BRCA1 promoter methylation is significantly associated with risk of incident triple-negative breast cancer and high-grade serous ovarian cancer, with potential implications for prediction of these cancers. These findings warrant further research to determine if constitutional methylation of tumor suppressor genes are pancancer risk factors.”
Per E. Lønning, MD, PhD, of the Department of Clinical Science, University of Bergen, Norway, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by the Norwegian Research Council and the Norwegian Health Region West. For full disclosures of the study authors, visit jamanetwork.com.
