Strickland Kyle C, Wallen Zachary D, Ko Heidi C, Green Michelle F, Dillard Alicia, Pabla Sarabjot, Hastings Stephanie, Roos Alison, Jensen Taylor J, Eisenberg Marcia, Caveney Brian J, Ramkissoon Shakti, Severson Eric A, Previs Rebecca A
Labcorp, 10 Moore Dr, Durham, NC, 27703, USA.
Department of Pathology, Duke University Medical Center, Duke Cancer Institute, Durham, NC, 27710, USA.
Sci Rep. 2025 Aug 12;15(1):29523. doi: 10.1038/s41598-025-15156-9.
High-grade serous ovarian carcinoma (HGSOC) is a molecularly heterogeneous and lethal malignancy, with late-stage diagnosis contributing to high risk of recurrence and poor clinical outcomes. Although homologous recombination (HR) deficiency and retinoblastoma gene (RB1) expression have been implicated in prognosis, their combined role in shaping tumor biology and survival outcomes is not well defined. To investigate the relationship between HR status and RB1 expression and explore their potential as a combined prognostic marker, we analyzed data from two cohorts: (1) 272 HGSOC cases from The Cancer Genome Atlas (TCGA) with RB1 mRNA expression data and HR status previously annotated by Takaya et al. (HR-deficient, HRD; HR-proficient, HRP), and (2) 226 clinical HGSOC cases profiled by comprehensive genomic and immune profiling (CGIP) at OmniSeq, categorized as either HR-intact (HRi) or harboring BRCA1/2 alterations (BRCAa). Cases were additionally stratified according to RB1 mRNA expression level as RB1-high (> 25th percentile; RBH) or RB1-low (≤ 25th percentile; RBL). HRP-RBH tumors (n = 120, 44.1%) were associated with significantly worse overall survival (OS) and progression free survival (PFS) compared to all other subgroups. Survival metrics were evaluated from the TCGA cohort and demonstrated that median OS for HRP-RBH was 35.9 mo, shorter than HRP-RBL (52.0 mo), HRD-RBL (57.1 mo), and HRD-RBH subgroups (53.3 mo; all p < 0.0001). PFS demonstrated a similar trend (15.1 mo vs. 20.6, 20.2 and 20.4 mo, respectively, p = 0.0021). HRP-RBH tumors also showed higher aneuploidy scores (median 18 vs. ≤ 10.5 in other subgroups, all p < 0.01). From the OmniSeq cohort, HRi-RBH tumors exhibited a distinct immune gene signature, including elevated mRNA expression of 213 differentially expressed genes and enrichment of pathways such as EMT, PI3K/AKT signaling, and interleukin signaling. Overall, this study suggests that molecular subtyping of HGSOC based on HR status and RB1 expression may provide valuable prognostic insight. HRP tumors with high RB1 expression represent a high-risk subgroup with a distinct molecular profile and poor clinical outcomes, underscoring the need for novel therapeutic strategies targeting this aggressive subset. These findings provide a foundation for future studies aimed at developing biomarkers and treatments tailored to this challenging subset of HGSOC patients.
高级别浆液性卵巢癌（HGSOC）是一种分子异质性且致命的恶性肿瘤，晚期诊断导致复发风险高且临床结局不佳。尽管同源重组（HR）缺陷和视网膜母细胞瘤基因（RB1）表达与预后有关，但其在塑造肿瘤生物学和生存结局中的联合作用尚不清楚。为了研究HR状态与RB1表达之间的关系，并探索它们作为联合预后标志物的潜力，我们分析了两个队列的数据：（1）来自癌症基因组图谱（TCGA）的272例HGSOC病例，具有RB1 mRNA表达数据和Takaya等人先前注释的HR状态（HR缺陷，HRD；HR proficient，HRP），以及（2）在OmniSeq通过综合基因组和免疫分析（CGIP）分析的226例临床HGSOC病例，分为HR完整（HRi）或携带BRCA1/2改变（BRCAa）。病例还根据RB1 mRNA表达水平分层为RB1高（>第25百分位数；RBH）或RB1低（≤第25百分位数；RBL）。与所有其他亚组相比，HRP-RBH肿瘤（n = 120，44.1%）的总生存期（OS）和无进展生存期（PFS）明显更差。从TCGA队列评估生存指标，结果表明HRP-RBH的中位OS为35.9个月，短于HRP-RBL（52.0个月）、HRD-RBL（57.1个月）和HRD-RBH亚组（53.3个月；所有p < 0.0001）。PFS显示出类似趋势（分别为15.1个月对20.6、20.2和20.4个月，p = 0.0021）。HRP-RBH肿瘤也显示出更高的非整倍体评分（中位数18对其他亚组≤10.5，所有p < 0.01）。在OmniSeq队列中，HRi-RBH肿瘤表现出独特的免疫基因特征，包括213个差异表达基因的mRNA表达升高以及EMT、PI3K/AKT信号传导和白细胞介素信号传导等通路的富集。总体而言，本研究表明基于HR状态和RB1表达对HGSOC进行分子亚分型可能提供有价值的预后见解。RB1表达高的HRP肿瘤代表一个高危亚组，具有独特的分子特征和较差的临床结局，强调需要针对这一侵袭性亚组的新型治疗策略。这些发现为未来旨在开发针对这一具有挑战性的HGSOC患者亚组的生物标志物和治疗方法的研究奠定了基础。
