Constitutional BRCA1 Methylation and Risk of Incident Triple-Negative Breast Cancer and High-grade Serous Ovarian Cancer

Abstract

IMPORTANCE About 25% of all triple-negative breast cancers (TNBCs) and 10% to 20% of high-grade serous ovarian cancers (HGSOCs) 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 TNBC or HGSOC is unknown.OBJECTIVE To assess the potential association between white blood cell BRCA1 promoter methylation and subsequent risk of incident TNBC and HGSOC. DESIGN, SETTING, AND PARTICIPANTSThis case-control study included women who were participating in the Women's Health Initiative study who had not received a diagnosis of either breast or ovarian cancer before study entrance. A total of 637 women developing incident TNBC and 511 women developing incident HGSOC were matched with cancer-free controls (1841 and 2982, respectively) in a nested case-control design. Cancers were confirmed after central medical record review. Blood samples, which were collected at entry, were analyzed for BRCA1 promoter methylation by massive parallel sequencing. The study was performed in the Mohn Cancer Research Laboratory (Bergen, Norway) between 2019 and 2022.MAIN OUTCOMES AND MEASURES Associations between BRCA1 methylation and incident TNBC and incident HGSOC were analyzed by Cox proportional hazards regression. RESULTSOf 2478 cases and controls in the TNBC group and 3493 cases and controls in the HGSOC group, respectively, 7 (0.3%) and 3 (0.1%) were American Indian or Alaska Native, 46 (1.9%) and 30 (0.9%) were Asian, 1 (0.04%) and 1 (0.03%) was Native Hawaiian or Pacific Islander, 326 (13.2%) and 125 (3.6%) were Black or African, 56 (2.3%) and 116 (3.3%) were Hispanic, 2046 (82.6%) and 3257 (93.2%) were White, and 35 (1.4%) and 35 (1.0%) were multiracial. Median (range) age at entry was 62 (50-79) years, with a median interval to diagnosis of 9 (TNBC) and 10 (HGSOC) years. Methylated BRCA1 alleles were present in 194 controls (5.5%). Methylation was associated with risk of incident TNBC (12.4% methylated; HR, 2.35; 95% CI, 1.70-3.23; P < .001) and incident HGSOC (9.4% methylated; HR, 1.93; 95% CI, 1.36-2.73; P < .001). Restricting analyses to individuals with more than 5 years between sampling and cancer diagnosis yielded similar results (TNBC: HR, 2.52; 95% CI, 1.75-3.63; P < .001; HGSOC: HR, 1.82; 95% CI, 1.22-2.72; P = .003). Across individuals, methylation was not haplotype-specific, arguing against an underlying cis-acting factor. Within individuals, BRCA1 methylation was observed on the same allele, indicating clonal expansion from a single methylation event. There was no association found between BRCA1 methylation and germline pathogenic variant status. CONCLUSIONS AND RELEVANCEThe results of this case-control suggest that constitutional normal tissue BRCA1 promoter methylation is significantly associated with risk of incident TNBC and HGSOC, with potential implications for prediction of these cancers. These findings warrant further research to determine if constitut...

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“…Similarly, inherited mutations in the breast cancer-1 ( BRCA1 ) gene increase risk of breast, ovarian and prostate cancer [ 5 ]. In addition, methylation of the promoter of BRCA1 is observed in a substantial proportion of breast cancers and women with BRCA1 promoter methylation in normal tissue throughout the body (due, probably, to early life events) have increased risk of triple-negative breast cancer and high-grade serous ovarian cancer [ 6 ]. Consequently, findings from studies of such familial syndromes are likely to generalise to much of the population.…”

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“…For now, constitutional epimutations cannot be used to adapt cancer prevention strategies, but they may help to guide BC screening in the future [ 4 ]. Indeed, mosaic BRCA1 promoter methylations (MBPM) are much more frequent than BRCA1 gPV in healthy women population (4–8% versus around 0.5 %), and several studies have shown that MBPM increase the risk of triple-negative or early-onset BC [ [5] , [6] , [7] , [8] , [15] ]. However, there is no consensus about the use of MBPM in clinical practice.…”

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“…Triple-negative breast cancer (TNBC) with a lack of expression of estrogen, progesterone, and human epidermal growth factor 2 receptors comprises approximately 15 to 20% of breast cancer cases (Alsughayer et al 2022;Sharifi et al 2021), which generally have deleterious mutations in breast cancer gene-1 (Lønning et al 2022). The higher risk of recurrence of TNBC compared to other subtypes of breast cancer and their very poor prognosis has made the treatment path very challenging.…”