Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types.
Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types.
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DOI：
10.1158/1078-0432.ccr-10-0199
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发表时间：
2010-10-01
期刊：
影响因子：
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通讯作者：
Hayes DN
中科院分区：
文献类型：
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作者：
Wilkerson MD;Yin X;Hoadley KA;Liu Y;Hayward MC;Cabanski CR;Muldrew K;Miller CR;Randell SH;Socinski MA;Parsons AM;Funkhouser WK;Lee CB;Roberts PJ;Thorne L;Bernard PS;Perou CM;Hayes DN
肺鳞状细胞癌（SCC）的临床和遗传异质性和目前的诊断实践不充分的substratify这种异质性。一个强大的，基于生物学的SCC子分类可以描述这种变异性，并导致更精确的患者预后和管理。我们试图确定SCC mRNA表达亚型是否存在，在多个患者队列中是否可重复，以及是否具有临床相关性。在5个已发表的mRNA微阵列发现队列中，通过无监督共识聚类检测亚型，共382例SCC患者。一个独立的验证队列的56例SCC患者收集和微阵列分析。使用发现队列建立最近质心亚型预测器。预测并评价验证队列亚型以进行确认。通过统计学和生物信息学方法比较亚型生存结局、临床协变量和生物学过程。检测到原始型、经典型、分泌型和基础型四种肺SCC mRNA表达亚型，并进行独立验证（P < 0.001）。原始亚型的生存率最差（P < 0.05），是生存率的独立预测因子（P < 0.05）。肿瘤分化程度和患者性别与亚型相关。这些亚型的表达谱包含不同的生物学过程（原始增殖、经典异生素代谢、分泌免疫应答、基底细胞粘附）并提示不同的药理学干预。与肺模型系统的比较揭示了不同的亚型与细胞类型的对应关系。肺SCC由四种mRNA表达亚型组成，它们具有不同的生存结局、患者人群和生物学过程。亚型对患者进行分层，以获得更精确的预后和有针对性的研究。
Lung squamous cell carcinoma (SCC) is clinically and genetically heterogeneous and current diagnostic practices do not adequately substratify this heterogeneity. A robust, biologically-based SCC subclassification may describe this variability and lead to more precise patient prognosis and management. We sought to determine if SCC mRNA expression subtypes exist, are reproducible across multiple patient cohorts, and are clinically relevant. Subtypes were detected by unsupervised consensus clustering in five published discovery cohorts of mRNA microarrays, totaling 382 SCC patients. An independent validation cohort of 56 SCC patients was collected and assayed by microarrays. A nearest-centroid subtype predictor was built using discovery cohorts. Validation cohort subtypes were predicted and evaluated for confirmation. Subtype survival outcome, clinical covariates, and biological processes were compared by statistical and bioinformatic methods. Four lung SCC mRNA expression subtypes, named primitive, classical, secretory, and basal, were detected and independently validated (P < 0.001). The primitive subtype had the worst survival outcome (P < 0.05) and is an independent predictor of survival (P < 0.05). Tumor differentiation and patient sex were associated with subtype. The subtypes’ expression profiles contained distinct biological processes (primitive – proliferation, classical – xeniobiotics metabolism, secretory – immune response, basal – cell adhesion) and suggested distinct pharmacologic interventions. Comparison to lung model systems revealed distinct subtype to cell type correspondence. Lung SCC consists of four mRNA expression subtypes that have different survival outcomes, patient populations, and biological processes. The subtypes stratify patients for more precise prognosis and targeted research.