Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors
Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors
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DOI：
10.1200/jco.2005.03.8224
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发表时间：
2006-04-10
影响因子：
45.3
通讯作者：
Takahashi, T
中科院分区：
文献类型：
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作者：
Takeuchi, T;Tomida, S;Takahashi, T
方法对149例非小细胞肺癌患者(包括90例腺癌患者)的18,175个独特基因和3个主要基因变化靶点P53、表皮生长因子受体(EGFR)和K-ras基因的表达谱进行研究，以确定其与临床病理特征和基因本体(GO)术语的关系。我们的基于GO术语的特定生物过程、分子功能和细胞隔间的识别符清楚地显示了TRU类型中正常外周肺特征的保留，这与非TRU类型与细胞周期和增殖相关特征的显著关联形成了鲜明对比。虽然在TRU型中观察到EGFR突变的频率明显较高，但我们发现EGFR突变的存在是TRU型术后较短生存期的显著预测因素，与疾病分期无关。我们还能够在体内鉴定出一组在EGFR突变存在时显著上调的基因。结论本研究通过建立一个分子、基因和临床相关的表达谱定义的分类，揭示了肺癌，特别是腺癌的异质性。未来使用独立患者队列的研究有必要证实EGFR突变在TRU型腺癌中的预后意义。
PurposeThis study was conducted to gain insight into the relationship between expression profiles and underlying genetic changes, which are known to be important for the pathogenesis of lung cancers.MethodsExpression profiles of 18,175 unique genes and three major targets for genetic changes, p53, epidermal growth factor receptor (EGFR, and K-ras, were investigated in 149 patients with non-small-cell lung cancer, including 90 patients with adenocarcinoma to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms.ResultsThis study successfully established a basis for expression profile-defined classification, which can classify adenocarcinomas into two major types, terminal respiratory unit (TRU) type and non-TRU type. Our GO term-based identifier of particular biologic processes, molecular functions, and cellular compartments clearly showed characteristic retention of normal peripheral lung features in TRU type, in sharp contrast to the significant association of non-TRU type with cell cycling and proliferation-related features. While significantly higher frequency of EGFR mutation was observed in TRU type, we found that the presence of EGFR mutations was a significant predictor of shorter postoperative survival for TRU type, independent of disease stage. We were also able to identify a set of genes in vivo with significant upregulation in the presence of EGFR mutations.ConclusionThis study has shed light on heterogeneity in lung cancers, especially in adenocarcinomas, by establishing a molecularly, genetically, and clinically relevant, expression profile-defined classification. Future studies using independent patient cohorts are warranted to confirm the prognostic significance of EGFR mutations in TRU-type adenocarcinoma.