Tumor Biology

, Volume 37, Issue 2, pp 2193–2207 | Cite as

Combined analysis identifies six genes correlated with augmented malignancy from non-small cell to small cell lung cancer

  • Cheng Zhang
  • Li Min
  • Liyi Zhang
  • Yuanyuan Ma
  • Yue Yang
  • Chengchao Shou
Original Article


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.


Lung cancer Expression profiling Prognostic markers Risk signatures Cancer phenotype plasticity 





Squamous cell carcinoma


Large cell carcinoma


Small cell lung cancer


Overall survival


Relapse-free survival



We deeply appreciate Jiangyong Yu, Yong Han, and Fubing Tang for the kind provision of specimens and helpful suggestions on statistical analysis. This study was supported by the National 973 Program of China (2015CB553906).

Conflict of interest


Supplementary material

13277_2015_3938_Fig8_ESM.gif (147 kb)
Fig. S1

Hub genes’ relationship with patient survival and relapse-free survival assessed by ROC analysis. Predictive value of six hub genes for a death and b recurrence during follow-up were analyzed by ROC analysis (SPSS 17.0). AUC area under curve (GIF 147 kb)

13277_2015_3938_MOESM1_ESM.tif (5.9 mb)
High Resolution (TIFF 6075 kb)
13277_2015_3938_MOESM2_ESM.doc (66 kb)
Table S1 (DOC 66 kb)
13277_2015_3938_MOESM3_ESM.doc (35 kb)
Table S2 (DOC 35 kb)
13277_2015_3938_MOESM4_ESM.doc (48 kb)
Table S3 (DOC 47 kb)


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Cheng Zhang
    • 1
  • Li Min
    • 1
  • Liyi Zhang
    • 2
  • Yuanyuan Ma
    • 2
  • Yue Yang
    • 2
  • Chengchao Shou
    • 1
  1. 1.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular BiologyPeking University Cancer Hospital & InstituteBeijingChina
  2. 2.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery IIPeking University Cancer Hospital and InstituteBeijingChina

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