Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types
Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types
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DOI：
10.1158/1078-0432.ccr-19-0404
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发表时间：
2019-07-15
影响因子：
11.5
通讯作者：
Feng, Felix Y.
中科院分区：
文献类型：
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作者：
Chen, William S.;Alshalalfa, Mohammed;Feng, Felix Y.
目的：Rb通路中断具有很大的临床意义，因为它已被证明可以预测多种癌症的结局。我们试图开发一个转录组签名检测双等位基因RB1损失（RBS），可用于评估的临床意义RB1损失的泛cancer scale.Experimental设计：我们利用数据从癌细胞系百科全书（N = 995）开发的第一个泛癌转录组签名预测双等位基因RB1损失（RBS）。使用癌症基因组图谱（TCGA）泛癌症数据集（N = 11，007）验证模型准确性。然后使用RBS评估TCGA泛癌症和另外的转移性去势抵抗性前列腺癌（mCRPC）cohol.Results中双等位基因RB1丢失的临床相关性：RBS优于用于检测TCGA泛癌症中所有癌症类型的RB1双等位基因丢失的现有主要特征（AUC，0.89对0.66）。高RBS（RB1双等位基因丢失）与启动子高甲基化（P = 0.008）和基因体低甲基化（P = 0.002）相关，表明RBS可以检测表观遗传基因沉默。TCGA泛癌症临床分析显示，高RBS与短的无进展生存期（P < 0.00001）、总体生存期（P = 0.0004）和疾病特异性生存期（P < 0.00001）相关。在多变量分析中，高RBS预测TCGA泛癌患者的无进展生存期较短（P = 0.03），而预测mCRPC患者的总生存期较短（P = 0.004），这与RB1中DNA变异的数量无关。结论：我们的研究提供了第一个基于基因表达评估不同癌症类型中RB1双等位基因丢失的有效工具。RBS可用于分析具有或不具有DNA测序结果的数据集，以研究Rb通路中断的新兴预后和治疗意义。
Purpose: Rb-pathway disruption is of great clinical interest, as it has been shown to predict outcomes in multiple cancers. We sought to develop a transcriptomic signature for detecting biallelic RB1 loss (RBS) that could be used to assess the clinical implications of RB1 loss on a pan-cancer scale.Experimental Design: We utilized data from the Cancer Cell Line Encyclopedia (N = 995) to develop the first pancancer transcriptomic signature for predicting biallelic RB1 loss (RBS). Model accuracy was validated using The Cancer Genome Atlas (TCGA) Pan-Cancer dataset (N = 11,007). RBS was then used to assess the clinical relevance of biallelic RB1 loss in TCGA Pan-Cancer and in an additional metastatic castration-resistant prostate cancer (mCRPC) cohort.Results: RBS outperformed the leading existing signature for detecting RB1 biallelic loss across all cancer types in TCGA Pan-Cancer (AUC, 0.89 vs. 0.66). High RBS (RB1 biallelic loss) was associated with promoter hypermethylation (P = 0.008) and gene body hypomethylation (P = 0.002), suggesting RBS could detect epigenetic gene silencing. TCGA Pan-Cancer clinical analyses revealed that high RBS was associated with short progression-free (P < 0.00001), overall (P = 0.0004), and disease-specific (P < 0.00001) survival. On multivariable analyses, high RBS was predictive of shorter progression-free survival in TCGA Pan-Cancer (P = 0.03) and of shorter overall survival in mCRPC (P = 0.004) independently of the number of DNA alterations in RB1.Conclusions: Our study provides the first validated tool to assess RB1 biallelic loss across cancer types based on gene expression. RBS can be useful for analyzing datasets with or without DNA-sequencing results to investigate the emerging prognostic and treatment implications of Rb-pathway disruption.