BACKGROUND BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal/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. METHODS 2636 participants' data across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinico-pathological 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 two-sided. RESULTS 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, HR = 1.01, 95% CI = 0.87-1.16, P=0.98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87-1.18, P=0.96). 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 PCR and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66-0.97, P=0.02; OS: HR = 0.80, 95% CI = 0.63-1.00, P=0.05) on mixed-effects modelling. CONCLUSION BRCA1-methylated OC displays similar clinico-pathological 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.

中文翻译：

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卵巢癌中BRCA1启动子的甲基化和临床结局：一项单独的患者数据荟萃分析。

背景技术BRCA1甲基化与同源重组缺陷有关，后者是铂敏感性的生物标记。评估BRCA1甲基化输卵管/卵巢癌（OC）的研究并不能始终支持铂化疗后生存期的改善。我们在单个参与者数据的荟萃分析中检查了BRCA1-甲基化OC的特征。方法分析15项研究中2636名参与者的数据。BRCA1甲基化的肿瘤是根据其原始研究定义的。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了甲基化对总生存期（OS）和无进展生存期（PFS）的影响。所有统计检验都是双面的。结果430例（16.3％）肿瘤被BRCA1甲基化。BRCA1甲基化与年龄较小和晚期高级别浆液性OC有关。BRCA1甲基化和非BRCA1甲基化OC之间没有生存差异（中位PFS = 20.0 vs 18.5个月，HR = 1.01,95％CI = 0.87-1.16，P = 0.98;中位OS = 46.6 vs 48.0个月，HR = 1.02，95％CI = 0.87-1.18，P = 0.96）。在评估BRCA1 / 2突变的情况下（n = 1248），BRCA1甲基化没有比完整的BRCA1 / 2（BRCA1 / 2野生型非BRCA1甲基化）OC具有生存优势。研究使用不同的方法来定义BRCA1甲基化。使用甲基化特异性PCR和凝胶电泳确定BRCA1甲基化的情况（n = 834），可以提高生存率（PFS：HR = 0.80，95％CI = 0.66-0.97，P = 0.02; OS：HR = 0.80， 95％CI = 0.63-1.00，P = 0.05）。结论BRCA1甲基化OC与BRCA1突变的OC具有相似的临床病理特征，但与生存率无关。BRCA1甲基化分析中的异质性会影响关联。完善这些检测方法可能会更好地识别BRCA1功能沉默并改善患者预后的病例。