Identification of gene signatures and molecular markers for human lung cancer prognosis using an in vitro lung carcinogenesis system.
Identification of gene signatures and molecular markers for human lung cancer prognosis using an in vitro lung carcinogenesis system.
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DOI：
10.1158/1940-6207.capr-09-0084
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发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
Lotan R
中科院分区：
文献类型：
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作者：
Kadara H;Lacroix L;Behrens C;Solis L;Gu X;Lee JJ;Tahara E;Lotan D;Hong WK;Wistuba II;Lotan R
肺癌仍然是一种主要的致命恶性肿瘤。通过提高预测癌症患者生存的能力，可以降低这种疾病的死亡率。我们假设，构成体外人肺癌发生模型的细胞（包括正常、永生化、转化和致瘤性支气管上皮细胞）之间的基因差异表达与非小细胞肺癌（NSCLC）的临床结果有关。对上述细胞的转录组进行多维缩放、微阵列和功能通路分析，并结合整合基因组学，将微阵列数据与已发表的NSCLC数据集相结合。上调基因（n = 301）和下调基因（n = 358）在体外模型中表现出表达水平变化，并伴有癌症相关分子功能的进行性变化。这些基因的一个子集（n = 584）将肺腺癌临床样本（n = 361）分为两组，生存率有显著差异。功能阵列分析选择的6个基因UBE2C、TPX2、MCM2、MCM6、FEN1和SFN也对预后有影响。其中一个基因ube2c的mRNA和蛋白水平在非小细胞肺癌组织中相对于正常肺显著上调，并在肺病变中逐渐升高。此外，UBE2C阳性表达的I期NSCLC患者的总生存期和无进展生存期明显低于UBE2C阴性表达的患者。我们在体外模型上的研究已经鉴定出一个强大的六基因特征，这可能对预测肺腺癌患者的生存有价值。此外，其中一个基因UBE2C似乎是预测非小细胞肺癌生存的强有力的生物标志物。
Lung cancer continues to be a major deadly malignancy. The mortality of this disease could be reduced by improving the ability to predict cancer patients' survival. We hypothesized that genes differentially expressed among cells constituting an in vitro human lung carcinogenesis model consisting of normal, immortalized, transformed, and tumorigenic bronchial epithelial cells are relevant to the clinical outcome of non–small cell lung cancer (NSCLC). Multidimensional scaling, microarray, and functional pathways analyses of the transcriptomes of the above cells were done and combined with integrative genomics to incorporate the microarray data with published NSCLC data sets. Up-regulated (n = 301) and down-regulated genes (n = 358) displayed expression level variation across the in vitro model with progressive changes in cancer-related molecular functions. A subset of these genes (n = 584) separated lung adenocarcinoma clinical samples (n = 361) into two clusters with significant survival differences. Six genes, UBE2C, TPX2, MCM2, MCM6, FEN1, and SFN, selected by functional array analysis, were also effective in prognosis. The mRNA and protein levels of one these genes—UBE2C—were significantly up-regulated in NSCLC tissue relative to normal lung and increased progressively in lung lesions. Moreover, stage I NSCLC patients with positive UBE2C expression exhibited significantly poorer overall and progression-free survival than patients with negative expression. Our studies with this in vitro model have lead to the identification of a robust six-gene signature, which may be valuable for predicting the survival of lung adenocarcinoma patients. Moreover, one of those genes, UBE2C, seems to be a powerful biomarker for NSCLC survival prediction.