MicroRNA expression differentiates histology and predicts survival of lung cancer.
MicroRNA expression differentiates histology and predicts survival of lung cancer.
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DOI：
10.1158/1078-0432.ccr-09-1736
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发表时间：
2010-01-15
期刊：
影响因子：
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通讯作者：
Wang E
中科院分区：
文献类型：
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作者：
Landi MT;Zhao Y;Rotunno M;Koshiol J;Liu H;Bergen AW;Rubagotti M;Goldstein AM;Linnoila I;Marincola FM;Tucker MA;Bertazzi PA;Pesatori AC;Caporaso NE;McShane LM;Wang E
决定肺癌组织学的分子驱动因素在很大程度上是未知的。我们研究了microRNA （miR）表达谱是否可以区分组织学亚型并预测非小细胞肺癌的生存。我们分析了来自肺癌病因学环境与遗传学（EAGLE）研究的165例腺癌（AD）和125例鳞状细胞癌（SQ）组织样本中的miR表达，使用了包含440例人类成熟反义miR的定制寡核苷酸阵列。我们使用t检验和f检验比较miR表达谱，并使用全局排列检验解释多重检验。我们使用Spearman相关系数和线性回归模型评估miR表达与吸烟的关系，并使用log-rank检验、Cox比例风险和生存风险预测模型评估miR表达与临床结果的关系，考虑人口统计学和肿瘤特征。MiR表达谱在AD和SQ之间存在显著差异（总体p<0.0001），特别是在早期阶段，包括位于肺癌中最常改变的染色体位点上的MiR（例如，3p21-22）。大多数mir，包括let-7家族的所有成员，在SQ中被下调。在EAGLE样本和一组独立的肺癌病例中，QRT-PCR证实了主要发现。在SQ中，组织学比较中miRs低表达下调与死亡风险增加1.2 - 3.6倍相关。5-miR标记显著预测SQ的生存。我们确定了miR表达谱，该表达谱强烈区分AD和SQ，并具有预后意义。这些发现可能导致基于组织学的治疗方法。
The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histological subtypes and predict survival for non-small cell lung cancer. We analyzed miR expression in 165 adenocarcinoma (AD) and 125 squamous cell carcinoma (SQ) tissue samples from the Environmental And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t-tests and F-tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards and survival risk prediction models, accounting for demographic and tumor characteristics. MiR expression profiles strongly differed between AD and SQ (global p<0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were down-regulated in SQ. Major findings were confirmed by QRT-PCR in EAGLE samples and in an independent set of lung cancer cases. In SQ, low expression of miRs down-regulated in the histology comparison was associated with 1.2 to 3.6-fold increased mortality risk. A 5-miR signature significantly predicted survival for SQ. We identified a miR expression profile that strongly differentiated AD from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches.