A potential signature of eight long non-coding RNAs predicts survival in patients with non-small cell lung cancer

Journal of Translational Medicine

Jie Sun¹  Dapeng Hao¹  Haixiu Yang¹  Yinqiu Cui²  Xiaojun Wang¹  Dongfeng He³  Maoni Guo¹  Meng Zhou² 

[1] College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, People’s Republic of China;School of Life Sciences, Jilin University, Changchun 130012, People’s Republic of China;Department of Interventional Radiology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin 150040, Heilongjiang, People’s Republic of China

关键词: Signature;    Overall survival;    Non-small cell lung cancer;    Long non-coding RNA;   

Others  :  1221452
DOI  :  10.1186/s12967-015-0556-3

 received in 2015-03-02, accepted in 2015-06-01,  发布年份 2015

【 摘 要 】

Background

Accumulated evidence suggests that dysregulated expression of long non-coding RNAs (lncRNAs) may play a critical role in tumorigenesis and prognosis of cancer, indicating the potential utility of lncRNAs as cancer prognostic or diagnostic markers. However, the power of lncRNA signatures in predicting the survival of patients with non-small cell lung cancer (NSCLC) has not yet been investigated.

Methods

We performed an array-based transcriptional analysis of lncRNAs in large patient cohorts with NSCLC by repurposing microarray probes from the gene expression omnibus database. A risk score model was constructed based on the expression data of these eight lncRNAs in the training dataset of NSCLC patients and was subsequently validated in other two independent NSCLC datasets. The biological implications of prognostic lncRNAs were also analyzed using the functional enrichment analysis.

Results

An expression pattern of eight lncRNAs was found to be significantly associated with overall survival (OS) of NSCLC patients in the training dataset. With the eight-lncRNA signature, patients of the training dataset could be classified into high- and low-risk groups with significantly different OS (median survival 1.67 vs. 6.06 years, log-rank test p = 4.33E−09). The prognostic power of eight-lncRNA signature was further validated in other two non-overlapping independent NSCLC cohorts, demonstrating good reproducibility and robustness of this eight-lncRNA signature in predicting OS of NSCLC patients. Multivariate regression and stratified analysis suggested that the prognostic power of the eight-lncRNA signature was independent of clinical and pathological factors. Functional enrichment analyses revealed potential functional roles of the eight prognostic lncRNAs in tumorigenesis.

Conclusions

These findings indicate that the eight-lncRNA signature may be an effective independent prognostic molecular biomarker in the prediction of NSCLC patient survival.

【 授权许可】

   
2015 Zhou et al.

【 图 表 】

Figure1.

Figure2.

Figure3.

Figure4.

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011; 61(2):69-90.
• [2]She J, Yang P, Hong Q, Bai C. Lung cancer in China: challenges and interventions. Chest. 2013; 143(4):1117-1126.
• [3]Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K et al.. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008; 455(7216):1069-1075.
• [4]Cheetham SW, Gruhl F, Mattick JS, Dinger ME. Long noncoding RNAs and the genetics of cancer. Br J Cancer. 2013; 108(12):2419-2425.
• [5]Ma L, Bajic VB, Zhang Z. On the classification of long non-coding RNAs. RNA Biol. 2013; 10(6):925-933.
• [6]Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014; 15(1):7-21.
• [7]Wang KX, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011; 43(6):904-914.
• [8]Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014; 505(7483):344-352.
• [9]Kornienko AE, Guenzl PM, Barlow DP, Pauler FM. Gene regulation by the act of long non-coding RNA transcription. BMC Biol. 2013; 11:59. BioMed Central Full Text
• [10]Maass PG, Luft FC, Bahring S. Long non-coding RNA in health and disease. J Mol Med. 2014; 92(4):337-346.
• [11]Qiu MT, Hu JW, Yin R, Xu L. Long noncoding RNA: an emerging paradigm of cancer research. Tumour Biol. 2013; 34(2):613-620.
• [12]Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov. 2011; 1(5):391-407.
• [13]Tang JY, Lee JC, Chang YT, Hou MF, Huang HW, Liaw CC et al.. Long noncoding RNAs-related diseases, cancers, and drugs. Sci World J. 2013; 2013:943539.
• [14]Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ et al.. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010; 464(7291):1071-1076.
• [15]Ge X, Chen Y, Liao X, Liu D, Li F, Ruan H et al.. Overexpression of long noncoding RNA PCAT-1 is a novel biomarker of poor prognosis in patients with colorectal cancer. Med Oncol. 2013; 30(2):588.
• [16]Hauptman N, Glavac D. Long non-coding RNA in cancer. Int J Mol Sci. 2013; 14(3):4655-4669.
• [17]Zhang H, Chen Z, Wang X, Huang Z, He Z, Chen Y. Long non-coding RNA: a new player in cancer. J Hematol Oncol. 2013; 6:37. BioMed Central Full Text
• [18]Zhang W, Huang C, Gong Z, Zhao Y, Tang K, Li X et al.. Expression of LINC00312, a long intergenic non-coding RNA, is negatively correlated with tumor size but positively correlated with lymph node metastasis in nasopharyngeal carcinoma. J Mol Histol. 2013; 44(5):545-554.
• [19]Li J, Chen Z, Tian L, Zhou C, He MY, Gao Y et al.. LncRNA profile study reveals a three-lncRNA signature associated with the survival of patients with oesophageal squamous cell carcinoma. Gut. 2014; 63(11):1700-1710.
• [20]Chen J, Wang R, Zhang K, Chen LB. Long non-coding RNAs in non-small cell lung cancer as biomarkers and therapeutic targets. J Cell Mol Med. 2014; 18(12):2425-2436.
• [21]Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM et al.. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003; 22(39):8031-8041.
• [22]White NM, Cabanski CR, Silva-Fisher JM, Dang HX, Govindan R, Maher CA. Transcriptome sequencing reveals altered long intergenic non-coding RNAs in lung cancer. Genome Biol. 2014; 15(8):429. BioMed Central Full Text
• [23]Nie FQ, Zhu Q, Xu TP, Zou YF, Xie M, Sun M et al.. Long non-coding RNA MVIH indicates a poor prognosis for non-small cell lung cancer and promotes cell proliferation and invasion. Tumour Biol. 2014; 35(8):7587-7594.
• [24]Zhang XQ, Sun S, Lam KF, Kiang KM, Pu JK, Ho AS et al.. A long non-coding RNA signature in glioblastoma multiforme predicts survival. Neurobiol Dis. 2013; 58:123-131.
• [25]Hu Y, Chen HY, Yu CY, Xu J, Wang JL, Qian J et al.. A long non-coding RNA signature to improve prognosis prediction of colorectal cancer. Oncotarget. 2014; 5(8):2230-2242.
• [26]Meng J, Li P, Zhang Q, Yang Z, Fu S. A four-long non-coding RNA signature in predicting breast cancer survival. J Exp Clin Cancer Res. 2014; 33(1):84. BioMed Central Full Text
• [27]Zhao W, Luo J, Jiao S. Comprehensive characterization of cancer subtype associated long non-coding RNAs and their clinical implications. Sci Rep. 2014; 4:6591.
• [28]Yang J, Lin J, Liu T, Chen T, Pan S, Huang W et al.. Analysis of lncRNA expression profiles in non-small cell lung cancers (NSCLC) and their clinical subtypes. Lung Cancer. 2014; 85(2):110-115.
• [29]Botling J, Edlund K, Lohr M, Hellwig B, Holmberg L, Lambe M et al.. Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis, and tissue microarray validation. Clin Cancer Res Off J Am Assoc Cancer Res. 2013; 19(1):194-204.
• [30]Okayama H, Kohno T, Ishii Y, Shimada Y, Shiraishi K, Iwakawa R et al.. Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. Cancer Res. 2012; 72(1):100-111.
• [31]Der SD, Sykes J, Pintilie M, Zhu CQ, Strumpf D, Liu N et al.. Validation of a histology-independent prognostic gene signature for early-stage, non-small-cell lung cancer including stage IA patients. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2014; 9(1):59-64.
• [32]Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 2003; 31(4):e15.
• [33]Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U et al.. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003; 4(2):249-264.
• [34]Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F et al.. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 2012; 22(9):1760-1774.
• [35]Zhang X, Sun S, Pu JK, Tsang AC, Lee D, Man VO et al.. Long non-coding RNA expression profiles predict clinical phenotypes in glioma. Neurobiol Dis. 2012; 48(1):1-8.
• [36]Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D et al.. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med. 2004; 350(18):1828-1837.
• [37]da Huang W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009; 37(1):1-13.
• [38]Sanchez-Palencia A, Gomez-Morales M, Gomez-Capilla JA, Pedraza V, Boyero L, Rosell R et al.. Gene expression profiling reveals novel biomarkers in nonsmall cell lung cancer. Int J Cancer. 2011; 129(2):355-364.
• [39]Guo NL, Wan YW. Pathway-based identification of a smoking associated 6-gene signature predictive of lung cancer risk and survival. Artif Intell Med. 2012; 55(2):97-105.
• [40]Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics. 2000; 56(2):337-344.
• [41]Merico D, Isserlin R, Stueker O, Emili A, Bader GD. Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS One. 2010; 5(11):e13984.
• [42]Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D et al.. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11):2498-2504.
• [43]Kratz JR, Jablons DM. Genomic prognostic models in early-stage lung cancer. Clin Lung Cancer. 2009; 10(3):151-157.
• [44]Zhu CQ, Pintilie M, John T, Strumpf D, Shepherd FA, Der SD et al.. Understanding prognostic gene expression signatures in lung cancer. Clin Lung Cancer. 2009; 10(5):331-340.
• [45]Gibb EA, Vucic EA, Enfield KS, Stewart GL, Lonergan KM, Kennett JY et al.. Human cancer long non-coding RNA transcriptomes. PLoS One. 2011; 6(10):e25915.
• [46]Su X, Malouf GG, Chen Y, Zhang J, Yao H, Valero V et al.. Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes. Oncotarget. 2014; 5(20):9864-9876.
• [47]Du Z, Fei T, Verhaak RG, Su Z, Zhang Y, Brown M et al.. Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nat Struct Mol Biol. 2013; 20(7):908-913.
• [48]Subramanian J, Simon R. Gene expression-based prognostic signatures in lung cancer: ready for clinical use? J Natl Cancer Inst. 2010; 102(7):464-474.
• [49]Skarin AT, Herbst RS, Leong TL, Bailey A, Sugarbaker D. Lung cancer in patients under age 40. Lung Cancer. 2001; 32(3):255-264.
• [50]Hsu CL, Chen KY, Shih JY, Ho CC, Yang CH, Yu CJ et al.. Advanced non-small cell lung cancer in patients aged 45 years or younger: outcomes and prognostic factors. BMC Cancer. 2012; 12:241. BioMed Central Full Text
• [51]Chen KY, Chang CH, Yu CJ, Kuo SH, Yang PC. Distribution according to histologic type and outcome by gender and age group in Taiwanese patients with lung carcinoma. Cancer. 2005; 103(12):2566-2574.
• [52]Kalemkerian GP, Akerley W, Bogner P, Borghaei H, Chow LQ, Downey RJ et al.. Small cell lung cancer. J Natl Compr Canc Netw. 2013; 11(1):78-98.
• [53]Hangauer MJ, Vaughn IW, McManus MT. Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. PLoS Genet. 2013; 9(6):e1003569.