The role of normal tissue gene promoter methylation in cancer risk is poorly understood.

To assess associations between normal tissue BRCA1 methylation and ovarian cancer risk.

2 case–control (initial and validation) studies.

2 hospitals in Norway (patients) and a population-based study (control participants).

934 patients and 1698 control participants in the initial study; 607 patients and 1984 control participants in the validation study.

All patients had their blood sampled before chemotherapy. White blood cell (WBC) BRCA1 promoter methylation was determined by using methylation-specific quantitative polymerase chain reaction, and the percentage of methylation-positive samples was compared between population control participants and patients with ovarian cancer, including the subgroup with high-grade serous ovarian cancer (HGSOC).

In the initial study, BRCA1 methylation was more frequent in patients with ovarian cancer than control participants (6.4% vs. 4.2%; age-adjusted odds ratio [OR], 1.83 [95% CI, 1.27 to 2.63]). Elevated methylation, however, was restricted to patients with HGSOC (9.6%; OR, 2.91 [CI, 1.85 to 4.56]), in contrast to 5.1% and 4.0% of patients with nonserous and low-grade serous ovarian cancer (LGSOC), respectively. These findings were replicated in the validation study (methylation-positive status in 9.1% of patients with HGSOC vs. 4.3% of control participants—OR, 2.22 [CI 1.40 to 3.52]—4.1% of patients with nonserous ovarian cancer, and 2.7% of those with LGSOC). The results were not influenced by tumor burden, storage time, or WBC subfractions. In separate analyses of young women and newborns, BRCA1 methylation was detected in 4.1% (CI, 1.8% to 6.4%) and 7.0% (CI, 5.0% to 9.1%), respectively.

Patients with ovarian cancer were recruited at the time of diagnosis in a hospital setting.

Constitutively normal tissue BRCA1 promoter methylation is positively associated with risk for HGSOC.

Norwegian Cancer Society.

正常组织基因启动子甲基化在癌症风险中的作用了解甚少。

评估正常组织BRCA1甲基化与卵巢癌风险之间的关联。

2个病例对照（初始和验证）研究。

挪威的2所医院（患者）和一项基于人群的研究（对照组）。

初始研究中有934例患者和1698例对照参与者；607名患者和1984名对照参与者参加了验证研究。

所有患者在化疗前均进行了血液采样。使用甲基化特异性定量聚合酶链反应测定白细胞（WBC）BRCA1启动子的甲基化，并比较人群控制参与者和卵巢癌患者（包括高浆液性卵巢癌亚组）患者的甲基化阳性样本百分比癌症（HGSOC）。

在最初的研究中，卵巢癌患者中BRCA1甲基化的频率高于对照组（6.4％比4.2％；年龄校正后的优势比[OR]为1.83 [95％CI为1.27至2.63]）。但是，甲基化水平升高仅限于HGSOC患者（9.6％； OR为2.91 [CI，1.85至4.56]），而非浆液性和低度浆液性卵巢癌（LGSOC）的患者分别为5.1％和4.0％，分别。这些发现在验证研究中得到了重复（HGSOC患者中9.1％的对照组参与者的甲基化阳性率为4.3％，对照组，OR，2.22 [CI 1.40至3.52]，非浆液性卵巢癌的患者为4.1％和2.7％ LGSOC的人）。结果不受肿瘤负荷，保存时间或WBC亚组分的影响。在对年轻妇女和新生儿的单独分析中，BRCA1 甲基化分别检出为4.1％（CI，1.8％至6.4％）和7.0％（CI，5.0％至9.1％）。

确诊时在医院内招募卵巢癌患者。

组成性正常组织BRCA1启动子甲基化与HGSOC风险正相关。

挪威癌症协会。