Spectral Clustering of Microarray Data Elucidates the Roles of Microenvironment Remodeling and Immune Responses in Survival of Head and Neck Squamous Cell Carcinoma
Spectral Clustering of Microarray Data Elucidates the Roles of Microenvironment Remodeling and Immune Responses in Survival of Head and Neck Squamous Cell Carcinoma
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DOI：
10.1200/jco.2009.24.8724
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发表时间：
2010-06-10
影响因子：
45.3
通讯作者：
Kalna, Gabriela
中科院分区：
文献类型：
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作者：
Thurlow, Johanna K.;Murillo, Claudia L. Pena;Kalna, Gabriela
PurposeTo确定功能相关的预后基因集头颈部鳞状细胞癌（HNSCC）的微阵列data.Patients和MethodsMicroarray分析的无监督统计分析进行了14个正常的口腔上皮和71例HNSCC患者的结果数据。谱聚类（SC）分析的数据集确定了多个载体代表不同方面的基因表达异质性样品之间。载体基因列表的基因本体（GO）分析鉴定了在定义的生物途径内显著富集的基因集。这些预后意义建立了考克斯生存analysis.ResultsThe最有影响力的SC载体是V2和V3。V2将正常与肿瘤样品分开。V2基因列表的GO分析鉴定了HNSCC之间具有异质性表达的途径，特别是粘着斑（FA）/细胞外基质重塑和精氨酸-细胞因子受体（CR）相互作用。V3基因列表的类似分析确定了CR途径的进一步异质性。V2 CR基因代表先天性免疫应答，而V3 CR基因的高表达代表不依赖于人乳头瘤病毒状态的适应性免疫应答。生存分析表明，FA基因集是预后不良的结果，而CR基因集的适应性免疫反应的分类是预后良好的结果。一个组合的FA&CR模型显着超过了目前的临床分类器的性能（P <0.001，在我们的队列，重要的是，P = 0.007在一个独立的队列60 HNSCCs）。进一步的大规模研究将确定这些基因集在HNSCC临床管理中的有用性。
PurposeTo identify functionally related prognostic gene sets for head and neck squamous cell carcinoma (HNSCC) by unsupervised statistical analysis of microarray data.Patients and MethodsMicroarray analysis was performed on 14 normal oral epithelium and 71 HNSCCs from patients with outcome data. Spectral clustering (SC) analysis of the data set identified multiple vectors representing distinct aspects of gene expression heterogeneity between samples. Gene ontology (GO) analysis of vector gene lists identified gene sets significantly enriched within defined biologic pathways. The prognostic significance of these was established by Cox survival analysis.ResultsThe most influential SC vectors were V2 and V3. V2 separated normal from tumor samples. GO analysis of V2 gene lists identified pathways with heterogeneous expression between HNSCCs, notably focal adhesion (FA)/extracellular matrix remodeling and cytokine-cytokine receptor (CR) interactions. Similar analysis of V3 gene lists identified further heterogeneity in CR pathways. V2CR genes represent an innate immune response, whereas high expression of V3CR genes represented an adaptive immune response that was not dependent on human papillomavirus status. Survival analysis demonstrated that the FA gene set was prognostic of poor outcome, whereas classification for adaptive immune response by the CR gene set was prognostic of good outcome. A combined FA&CR model dramatically exceeded the performance of current clinical classifiers (P < .001 in our cohort and, importantly, P = .007 in an independent cohort of 60 HNSCCs).ConclusionThe application of SC and GO algorithms to HNSCC microarray data identified gene sets highly significant for predicting patient outcome. Further large-scale studies will establish the usefulness of these gene sets in the clinical management of HNSCC.