Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
Department of Natural Sciences, Middlesex University, Hendon, London NW4 4BT, UK.
J Natl Cancer Inst. 2020 Dec 14;112(12):1190-1203. doi: 10.1093/jnci/djaa070.
BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal and ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data.
Data of 2636 participants across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinicopathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were 2-sided.
430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage, high-grade serous OC. There were no survival differences between BRCA1-methylated and non-BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, hazard ratio [HR] = 1.01, 95% CI = 0.87 to 1.16; P = .98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87 to 1.18; P = .96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2-intact (BRCA1/2 wild-type non-BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific polymerase chain reaction and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66 to 0.97; P = .02; OS: HR = 0.80, 95% CI = 0.63 to 1.00; P = .05) on mixed-effects modeling.
BRCA1-methylated OC displays similar clinicopathological features to BRCA1-mutated OC but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes.
BRCA1 甲基化与同源重组缺陷有关，后者是铂类敏感性的生物标志物。评估 BRCA1 甲基化输卵管和卵巢癌（OC）的研究并未一致支持铂类化疗后生存改善。我们通过个体参与者数据的荟萃分析来检查 BRCA1 甲基化 OC 的特征。
对 15 项研究中的 2636 名参与者的数据进行了分析。根据原始研究定义 BRCA1 甲基化肿瘤。评估 BRCA1 甲基化与临床病理特征之间的关联。使用混合效应模型检查甲基化对总生存期（OS）和无进展生存期（PFS）的影响。所有统计检验均为双侧。
430（16.3%）个肿瘤为 BRCA1 甲基化。BRCA1 甲基化与较年轻的年龄和晚期、高级别浆液性 OC 有关。BRCA1 甲基化和非 BRCA1 甲基化 OC 之间的生存无差异（中位 PFS=20.0 与 18.5 个月，HR=1.01，95%CI=0.87 至 1.16；P=0.98；中位 OS=46.6 与 48.0 个月，HR=1.02，95%CI=0.87 至 1.18；P=0.96）。在评估 BRCA1/2 突变的情况下（n=1248），BRCA1 甲基化与 BRCA1/2 完整（BRCA1/2 野生型非 BRCA1 甲基化）OC 相比，无生存优势。研究采用不同的方法来定义 BRCA1 甲基化。在使用甲基化特异性聚合酶链反应和凝胶电泳确定 BRCA1 甲基化的情况下（n=834），它与生存改善相关（PFS：HR=0.80，95%CI=0.66 至 0.97；P=0.02；OS：HR=0.80，95%CI=0.63 至 1.00；P=0.05）在混合效应模型上。
BRCA1 甲基化 OC 显示出与 BRCA1 突变 OC 相似的临床病理特征，但与生存无关。BRCA1 甲基化测定中的异质性会影响关联。改进这些测定方法可能会更好地识别 BRCA1 功能沉默的病例，并改善患者的预后。
