Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria.
Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Clin Epigenetics. 2024 Nov 27;16(1):171. doi: 10.1186/s13148-024-01781-0.
In high-grade ovarian cancer (HGOC), determination of homologous recombination deficiency (HRD) status is commonly used in routine practice to predict response to platinum-based therapy or poly (ADP-ribose) polymerase inhibitors (PARPi). Here we tested the hypothesis that BRCA loss of function (LOF) due to epigenetic or genetic aberrations is a better predictor for the clinical outcome than HRD. One hundred thirty-one HGOC tissues were tested for BRCA DNA-methylation, BRCA mutations, HRD and BRCA1 mRNA expression, followed by a comprehensive survival analysis.
BRCA1-methylation was detected in 11% of the tumors, exclusively in BRCA1-wild-type (wt) HGOCs. BRCA1-methylated tumors (BRCA1-meth) had HRD-scores similar to those of BRCA-mutated (mut) tumors, and higher compared to unmethylated-BRCA-wt tumors (BRCA-wt-unmeth; P < 0.001). Platinum-refractory or -resistant HGOCs at first recurrence were all BRCA-unmeth cancers. Only one of the BRCA-mut cancers had a platinum-resistant recurrence. Thus, 99% of relapses in cancers with epigenetic or genetic BRCA-alterations were platinum-sensitive. Multivariate analysis confirmed BRCA-LOF as an independent predictor of progression-free survival (PFS) and overall survival (OS), whereas HRD-status had no predictive value for PFS and OS. Patients with BRCA-wt-unmeth cancers had the worst outcome compared to patients with cancers harboring epigenetic or genetic BRCA-alterations (PFS: P = 0.007; OS: P = 0.022). Most importantly, the BRCA-wt-unmeth subfraction of HRD-positive HGOCs exhibited the same poor survival as the entire HRD-negative cohort.
In HGOC BRCA mutational status together with BRCA1-methylation exhibit the best predictive power for favorable clinical outcome and thus high sensitivity to platinum-based therapy, whereas BRCA-unrelated HRD positivity was not associated with improved platinum sensitivity.
在高级别卵巢癌（HGOC）中，同源重组缺陷（HRD）状态的确定通常用于常规实践，以预测对铂类治疗或聚（ADP-核糖）聚合酶抑制剂（PARPi）的反应。在这里，我们检验了这样一个假设，即由于表观遗传或遗传异常导致的 BRCA 功能丧失（LOF）比 HRD 更能预测临床结果。对 131 个 HGOC 组织进行了 BRCA 基因甲基化、BRCA 突变、HRD 和 BRCA1 mRNA 表达检测，随后进行了全面的生存分析。
在 11%的肿瘤中检测到 BRCA1 甲基化，仅存在于 BRCA1 野生型（wt）HGOC 中。BRCA1 甲基化肿瘤（BRCA1-meth）的 HRD 评分与 BRCA 突变（mut）肿瘤相似，且高于未甲基化的 BRCA1-wt 肿瘤（BRCA-wt-unmeth；P<0.001）。首次复发时铂类耐药或铂类难治性 HGOC 均为 BRCA-unmeth 癌症。仅有一个 BRCA 突变癌症出现铂类耐药复发。因此，99%的具有表观遗传或遗传 BRCA 改变的癌症的复发是铂类敏感的。多变量分析证实 BRCA-LOF 是无进展生存期（PFS）和总生存期（OS）的独立预测因子，而 HRD 状态对 PFS 和 OS 没有预测价值。与携带表观遗传或遗传 BRCA 改变的癌症患者相比，BRCA-wt-unmeth 癌症患者的预后最差（PFS：P=0.007；OS：P=0.022）。最重要的是，HRD 阳性的 HGOC 中 BRCA-wt-unmeth 亚群与整个 HRD 阴性队列的生存情况相同差。
在 HGOC 中，BRCA 突变状态与 BRCA1 甲基化一起，对临床结果具有最佳的预测能力，因此对铂类治疗高度敏感，而与 BRCA 无关的 HRD 阳性与提高铂类敏感性无关。
