Peter MacCallum Cancer Centre, Melbourne, Australia.
Department of Obstetrics and Gynecology, Bern University Hospital and University of Bern, Bern, Switzerland.
Clin Cancer Res. 2024 Aug 15;30(16):3481-3498. doi: 10.1158/1078-0432.CCR-23-3552.
The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).
RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss.
RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.
Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
本研究旨在评估 RB1 表达与卵巢癌各组织学类型的相关性，并探讨 BRCA1 或 BRCA2（BRCA）改变与 RB1 缺失共存对输卵管卵巢高级别浆液性癌（HGSC）患者生存的影响。
卵巢肿瘤组织分析联盟的 7436 例卵巢癌患者的组织标本进行了 RB1 蛋白免疫组化检测。我们对 1134 例 HGSC 患者进行了 RB1 表达和种系 BRCA 状态的检测，并将基因型与总生存期（OS）、肿瘤浸润 CD8+淋巴细胞和转录组亚型相关联。我们利用 CRISPR-Cas9 技术在携带 BRCA1 改变和不携带 BRCA1 改变的 HGSC 细胞中敲除 RB1，以模拟与治疗反应相关的共缺失。对 126 例原发性 HGSC 患者进行全基因组和转录组数据分析，以鉴定同时存在 BRCA 缺陷和 RB1 缺失的肿瘤。
RB1 缺失与 HGSC 的 OS 延长相关，但与子宫内膜样卵巢癌的预后较差相关。与单独存在任何一种改变的患者相比，同时存在 RB1 缺失和致病性种系 BRCA 变异的 HGSC 患者具有更好的 OS，其中位 OS 是那些既无致病性 BRCA 变异又保留 RB1 表达的患者的三倍（9.3 年 vs. 3.1 年）。BRCA1 改变的细胞中 RB1 敲除后，对顺铂和紫杉醇的敏感性增强。RB1 缺失和 BRCA 缺失的联合与增强的 IFN 反应、细胞周期失调和减少的上皮间质转化的转录标记物相关。CD8+淋巴细胞在同时缺失 RB1 和 BRCA 的 HGSC 中最为常见。
RB1 缺失与 BRCA 缺失共存与 HGSC 患者的超长生存期相关，这可能是由于更好的治疗反应和免疫刺激所致。
