K.G. Jebsen Centre for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
JAMA Oncol. 2022 Nov 1;8(11):1579-1587. doi: 10.1001/jamaoncol.2022.3846.
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.
To assess the potential association between white blood cell BRCA1 promoter methylation and subsequent risk of incident TNBC and HGSOC.
DESIGN, SETTING, AND PARTICIPANTS: This 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.
Associations between BRCA1 methylation and incident TNBC and incident HGSOC were analyzed by Cox proportional hazards regression.
Of 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.
The 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 constitutional methylation of tumor suppressor genes are pancancer risk factors.
约 25%的三阴性乳腺癌（TNBC）和 10%-20%的高级别浆液性卵巢癌（HGSOC）存在 BRCA1 启动子甲基化。虽然在一些个体的正常组织中已经观察到了 BRCA1 启动子的遗传性甲基化，但正常组织甲基化作为 TNBC 或 HGSOC 发病风险因素的潜在作用尚不清楚。
评估白细胞 BRCA1 启动子甲基化与随后发生的 TNBC 和 HGSOC 风险之间的潜在关联。
设计、设置和参与者：这项病例对照研究纳入了正在参加妇女健康倡议研究的女性，这些女性在研究入组前均未被诊断出患有乳腺癌或卵巢癌。637 例新发 TNBC 患者和 511 例新发 HGSOC 患者在巢式病例对照设计中与无癌对照者（分别为 1841 例和 2982 例）相匹配。癌症在中心病历审查后得到确认。在 2019 年至 2022 年期间，从入组时采集的血液样本通过大规模平行测序分析 BRCA1 启动子甲基化情况。该研究在莫恩癌症研究实验室（挪威卑尔根）进行。
通过 Cox 比例风险回归分析 BRCA1 甲基化与新发 TNBC 和新发 HGSOC 之间的关联。
在 TNBC 组的 2478 例病例和对照组以及 HGSOC 组的 3493 例病例和对照组中，分别有 7 例（0.3%）和 3 例（0.1%）为美洲印第安人或阿拉斯加原住民，46 例（1.9%）和 30 例（0.9%）为亚洲人，1 例（0.04%）和 1 例（0.03%）为夏威夷原住民或太平洋岛民，326 例（13.2%）和 125 例（3.6%）为黑人或非裔美国人，56 例（2.3%）和 116 例（3.3%）为西班牙裔，2046 例（82.6%）和 3257 例（93.2%）为白人，35 例（1.4%）和 35 例（1.0%）为多种族。入组时的中位年龄（范围）为 62（50-79）岁，中位至诊断间隔时间为 9（TNBC）和 10（HGSOC）年。194 例对照者（5.5%）存在 BRCA1 甲基化等位基因。甲基化与新发 TNBC（12.4%甲基化；HR，2.35；95%CI，1.70-3.23；P<0.001）和新发 HGSOC（9.4%甲基化；HR，1.93；95%CI，1.36-2.73；P<0.001）风险相关。将分析限制在采样与癌症诊断之间超过 5 年的个体中，得出了类似的结果（TNBC：HR，2.52；95%CI，1.75-3.63；P<0.001；HGSOC：HR，1.82；95%CI，1.22-2.72；P=0.003）。在个体中，甲基化不是单倍型特异性的，这表明不存在潜在的顺式作用因素。在个体内部，BRCA1 甲基化发生在同一等位基因上，表明单个甲基化事件的克隆扩增。未发现 BRCA1 甲基化与种系致病性变异状态之间存在关联。
这项病例对照研究的结果表明，正常组织中的 BRCA1 启动子甲基化与新发 TNBC 和 HGSOC 的风险显著相关，这可能对这些癌症的预测有意义。这些发现需要进一步研究，以确定肿瘤抑制基因的正常组织甲基化是否是泛癌风险因素。
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