Zhang Cheng, Min Li, Zhang Liyi, Ma Yuanyuan, Yang Yue, Shou Chengchao
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.
Tumour Biol. 2016 Feb;37(2):2193-207. doi: 10.1007/s13277-015-3938-5. Epub 2015 Sep 9.
With increased malignancy, lung cancer can be classified into adenocarcinoma (ADC), squamous cell carcinoma (SQC), large cell carcinoma (LCC), and the small cell subtype (SCLC); yet, elucidations to this augmented malignancy has not been addressed. In this study, we elucidated the molecular diversity among these subtypes by investigating large-scale sequencing datasets. Among genes upregulated from normal, ADC, SQC, LCC to SCLC, six hub genes were found closely correlated with adverse clinical outcome and were testified on cellular or tissue level with quantitative RT-PCR. Cox regression model was then built to generate a risk signature. The possible linkages among these genes were also explored. Transcript levels of BUB1, E2F1, ESPL1, GTSE1, RAB3B, and U2AF2 were found significantly elevated from normal, ADC, SQC, LCC to SCLC. Overexpression of one or multiple of these genes was correlated with adverse overall survival (OS) and relapse-free survival (RFS) in the whole patient cohort or groups stratified according to clinical variables, while most of all six genes were independent prognostic factors. When used as a six-gene risk signature, patients with high signature score displayed more unfavorable clinical variables and poorer outcome. Tight regulative relationships were found within these genes, while BUB1 and E2F1 were likely to be the drivers. We considered the augmented malignancy from non-small cell lung cancer (NSCLC) to SCLC might be due to the elevation of these six genes. We believe these genes were powerful cancer prognostic markers and potential therapeutic targets in lung cancer; moreover, changes of their level might be correlated with lung cancer phenotype plasticity.
随着恶性程度的增加，肺癌可分为腺癌（ADC）、鳞状细胞癌（SQC）、大细胞癌（LCC）和小细胞亚型（SCLC）；然而，对于这种恶性程度增加的原因尚未有明确解释。在本研究中，我们通过调查大规模测序数据集阐明了这些亚型之间的分子多样性。在从正常组织、ADC、SQC、LCC到SCLC上调的基因中，发现六个枢纽基因与不良临床结局密切相关，并通过定量逆转录聚合酶链反应在细胞或组织水平上得到验证。然后建立Cox回归模型以生成风险特征。还探索了这些基因之间可能的联系。发现BUB1、E2F1、ESPL1、GTSE1、RAB3B和U2AF2的转录水平从正常组织、ADC、SQC、LCC到SCLC显著升高。在整个患者队列或根据临床变量分层的组中，这些基因中的一个或多个的过表达与不良总生存期（OS）和无复发生存期（RFS）相关，而所有六个基因中的大多数是独立的预后因素。当用作六基因风险特征时，高特征评分的患者表现出更不利的临床变量和更差的结局。在这些基因中发现了紧密的调控关系，而BUB1和E2F1可能是驱动因素。我们认为从非小细胞肺癌（NSCLC）到SCLC的恶性程度增加可能是由于这六个基因的升高。我们相信这些基因是强大的癌症预后标志物和肺癌潜在的治疗靶点；此外，它们水平的变化可能与肺癌表型可塑性相关。
