Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, Australia; CRUK Manchester Institute, The University of Manchester, Manchester, UK.
Ann Oncol. 2020 Sep;31(9):1240-1250. doi: 10.1016/j.annonc.2020.05.019. Epub 2020 May 28.
Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.
Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.
Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years.
The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
高级别浆液性卵巢癌（HGSOC）女性的中位总生存期（OS）约为 4 年，但患者之间的生存情况差异很大。目前尚无与预后相关的明确的基因表达特征。本研究旨在为 HGSOC 患者建立一个稳健的 OS 预后标志。
从 1455 个肿瘤和其他候选基因的荟萃分析中选择 513 个基因，使用 NanoString 技术从来自多个研究的 3769 名 HGSOC 女性的福尔马林固定石蜡包埋肿瘤组织中进行测量。弹性网络正则化用于生存分析，以建立 5 年 OS 的预测模型，该模型在 15 项研究中的 2702 个肿瘤上进行训练，并在 6 项研究中的 1067 个肿瘤上进行评估。
在协变量调整的单基因分析中，276 个基因的表达水平与 OS 相关（错误发现率 < 0.05）。排名前五的基因是 TAP1、ZFHX4、CXCL9、FBN1 和 PTGER3（P < 0.001）。表现最好的预后标志包括与治疗意义相关途径中富集的 101 个基因。基因表达评分每增加一个标准差，死亡风险增加两倍以上[风险比（HR）2.35，95%置信区间（CI）2.02-2.71；P < 0.001]。根据基因表达评分五分位数，中位生存时间[HR（95%CI）]为 9.5（8.3 至-）、5.4（4.6-7.0）、3.8（3.3-4.6）、3.2（2.9-3.7）和 2.3（2.1-2.6）年。
OTTA-SPOT（卵巢肿瘤组织分析联盟 - 卵巢肿瘤分层预后）基因表达标志可以通过识别最不可能实现 5 年生存的患者，改善临床试验中的风险分层。与结局相关的新鉴定基因也可能为靶向治疗方法的发展提供机会。
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