High-Risk Ovarian Cancer Based on 126-Gene Expression Signature Is Uniquely Characterized by Downregulation of Antigen Presentation Pathway
High-Risk Ovarian Cancer Based on 126-Gene Expression Signature Is Uniquely Characterized by Downregulation of Antigen Presentation Pathway
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DOI：
10.1158/1078-0432.ccr-11-2725
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发表时间：
2012-03-01
影响因子：
11.5
通讯作者：
Tanaka, Kenichi
中科院分区：
文献类型：
--
作者：
Yoshihara, Kosuke;Tsunoda, Tatsuhiko;Tanaka, Kenichi
目的：高级别浆液性卵巢癌不仅在临床预后方面，而且在分子水平上都是异质性的。我们的目的是建立一个新的风险分类系统的基础上的基因表达签名预测总生存期，从而提出新的治疗策略，为高风险患者。在这项由1,054名卵巢癌患者组成的6个微阵列数据集的大规模跨平台研究中，我们通过对日本数据集A（n = 260）应用弹性网和10倍交叉验证，开发了一种预测总生存率的基因表达特征。并评估了其他五组数据中的签名。随后，我们调查了高风险和低风险卵巢癌groups.Results之间的生物学特征的差异：弹性网络分析确定了一个126个基因的表达特征，用于预测卵巢癌患者的总生存率使用日本数据集A（多变量分析，P = 4 × 10（-20））。我们使用多变量分析验证了其预测能力与其他五个数据集（Tothill数据集，P = 1 x 10（-5）; Bonome数据集，P = 0.0033; Dressman数据集，P = 0.0016; TCGA数据集，P = 0.0027;日本数据集B，P = 0.021）。通过基因本体和途径分析，我们发现高危卵巢癌患者免疫应答相关基因的表达显著降低，尤其是抗原呈递途径。这种基于126个基因表达特征的风险分类是晚期高血压患者临床结局的准确预测因子。分级浆液性卵巢癌，并有可能为高级别浆液性卵巢癌患者开发新的治疗策略。临床癌症研究; 18（5）; 1374-85。（C）2012年AACR。
Purpose: High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients.Experimental Design: In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high-and low-risk ovarian cancer groups.Results: An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 x 10(-20)). We validated its predictive ability with five other data sets using multivariate analysis (Tothill's data set, P = 1 x 10(-5); Bonome's data set, P = 0.0033; Dressman's data set, P = 0.0016; TCGA data set, P = 0.0027; Japanese data set B, P = 0.021). Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response-related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients.Conclusions: This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients. Clin Cancer Res; 18(5); 1374-85. (C)2012 AACR.