PO.TB10.06 · 肿瘤生物学
基因组和空间单细胞分析揭示高级别浆液性卵巢癌中 BRCA 相关的肿瘤微环境特征
Genomic and spatial single-cell profiling reveals BRCA-linked tumor microenvironment signatures in high-grade serous ovarian carcinoma
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摘要 Abstract
中文摘要
背景：高级别浆液性卵巢癌（HGSOC）是卵巢癌中最具侵袭性和致死性的亚型，占卵巢癌相关死亡的 70% 以上。由于大多数病例在伴有远处转移的晚期才被诊断，早期检测和有效的治疗策略仍是一大挑战。尽管 PARP 抑制剂使 BRCA 突变或同源重组缺陷（HRD）患者获益，许多患者仍会产生治疗耐药。本研究使用空间单细胞转录组分析，探讨 BRCA 相关的免疫活化和肿瘤微环境（TME）特征如何影响治疗结果。
方法：从韩国妇科癌症库（KGCB）获得了共 89 例 HGSOC 样本，并具有全面的临床病理学注释。使用与外周血单个核细胞（PBMCs）匹配的肿瘤样本进行全基因组测序（WGS），以识别体细胞和种系基因组改变。构建组织微阵列（TMAs），并使用 NanoString 的空间单细胞 RNA 测序平台（Human Discovery Panel，6,000 个基因）进行分析，以表征 TME 内的空间异质性。
结果：WGS 分析揭示了与 BRCA 突变状态相关的不同基因组改变模式，凸显了关键癌症相关通路的差异。空间单细胞分析展示了异质性的肿瘤-免疫-基质相互作用，并识别出 BRCA 相关的 TME 重塑模式。与 BRCA 野生型患者相比，BRCA 突变患者表现出更高的化疗敏感性（p=0.045）以及显著更长的无进展间期（PFI，p=0.018）、无复发生存（RFS，p=0.022）和总生存（OS，p=0.032）。Kaplan-Meier 分析证实了根据 BRCA 突变状态存在显著的 OS 差异（p=0.009），且化疗耐药强烈影响 RFS 和 OS（p=0.000）。
结论：HGSOC 中的 BRCA 突变与增强的化疗敏感性和改善的生存结果密切相关。整合的 WGS 和空间单细胞分析揭示了塑造治疗反应的 BRCA 相关基因组特征和 TME 重塑模式。这些发现凸显了将 BRCA 状态、基因组分析和空间 TME 分析相结合作为 HGSOC 预后和个性化治疗策略预测性生物标志物的潜力。
查看英文原文 English abstract
Background: High-grade serous ovarian carcinoma (HGSOC) is the most aggressive and lethal subtype of ovarian cancer, accounting for more than 70% of ovarian cancer-related deaths. Because most cases are diagnosed at advanced stages with distant metastasis, early detection and effective treatment strategies remain a major challenge. Although PARP inhibitors benefit patients with BRCA mutations or homologous recombination deficiency (HRD), many still develop therapeutic resistance. This study investigates how BRCA-associated immune activation and tumor microenvironment (TME) features influence treatment outcomes using spatial single-cell transcriptomic profiling.
Methods: A total of 89 HGSOC samples were obtained from the Korea Gynecologic Cancer Bank (KGCB) with comprehensive clinicopathological annotation. Whole genome sequencing (WGS) was performed using tumor samples matched with peripheral blood mononuclear cells (PBMCs) to identify somatic and germline genomic alterations. Tissue microarrays (TMAs) were constructed and analyzed using NanoString's spatial single-cell RNA sequencing platform (Human Discovery Panel, 6,000 genes) to characterize spatial heterogeneity within the TME.
Results: WGS profiling revealed distinct genomic alteration patterns associated with BRCA mutation status, highlighting differences in key cancer-related pathways. Spatial single-cell analysis demonstrated heterogeneous tumor-immune-stromal interactions and identified BRCA-linked TME remodeling patterns. BRCA-mutated patients showed higher chemosensitivity (p=0.045) and significantly longer progression-free interval (PFI, p=0.018), recurrence-free survival (RFS, p=0.022), and overall survival (OS, p=0.032) compared with BRCA wild-type patients. Kaplan-Meier analysis confirmed significant OS differences according to BRCA mutation status (p=0.009), and chemotherapy resistance strongly affected both RFS and OS (p=0.000).
Conclusion: BRCA mutations in HGSOC are strongly associated with enhanced chemosensitivity and improved survival outcomes. Integrated WGS and spatial single-cell analysis revealed BRCA-related genomic features and TME remodeling patterns that shape therapeutic response. These findings highlight the potential of combining BRCA status, genomic profiling, and spatial TME analysis as predictive biomarkers for prognosis and personalized treatment strategies in HGSOC.
利益披露 Disclosure
J. Kim, None..
H. Shin, None..
Y. Kim, None..
Y. Lee, None..
J. Kim, None.