Identification of reproducible gene expression signatures in lung adenocarcinoma

BMC Bioinformatics

Tzu-Pin Lu¹  Eric Y Chuang²  James J Chen³ 

[1] YongLin Biomedical Engineering Center, National Taiwan University, Taipei, Taiwan

[2] Graduate Institute of Biomedical Engineering and Bioinformatics National Taiwan University, Taipei, Taiwan

[3] Graduate Institute of Biostatistics and Biostatistics Center, China Medical University, Taichung, Taiwan

关键词: Predictive biomarker;    Prognostic biomarker;    Pathway analysis;    Microarray;    Lung adenocarcinoma;   

Others  :  1087667
DOI  :  10.1186/1471-2105-14-371

 received in 2013-08-12, accepted in 2013-12-20,  发布年份 2013

【 摘 要 】

Background

Lung cancer is the leading cause of cancer-related death worldwide. Tremendous research efforts have been devoted to improving treatment procedures, but the average five-year overall survival rates are still less than 20%. Many biomarkers have been identified for predicting survival; challenges arise, however, in translating the findings into clinical practice due to their inconsistency and irreproducibility. In this study, we proposed an approach by identifying predictive genes through pathways.

Results

The microarrays from Shedden et al. were used as the training set, and the log-rank test was performed to select potential signature genes. We focused on 24 cancer-related pathways from 4 biological databases. A scoring scheme was developed by the Cox hazard regression model, and patients were divided into two groups based on the medians. Subsequently, their predictability and generalizability were evaluated by the 2-fold cross-validation and a resampling test in 4 independent datasets, respectively. A set of 16 genes related to apoptosis execution was demonstrated to have good predictability as well as generalizability in more than 700 lung adenocarcinoma patients and was reproducible in 4 independent datasets. This signature set was shown to have superior performances compared to 6 other published signatures. Furthermore, the corresponding risk scores derived from the set were found to associate with the efficacy of the anti-cancer drug ZD-6474 targeting EGFR.

Conclusions

In summary, we presented a new approach to identify reproducible survival predictors for lung adenocarcinoma, and the identified genes may serve as both prognostic and predictive biomarkers in the future.

【 授权许可】

   
2013 Lu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin 2012, 62(1):10-29.
• [2]Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA: Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008, 83(5):584-594.
• [3]Beer DG, Kardia SL, Huang CC, Giordano TJ, Levin AM, Misek DE, Lin L, Chen G, Gharib TG, Thomas DG, et al.: Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med 2002, 8(8):816-824.
• [4]Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, Joshi MB, Harpole D, Lancaster JM, Berchuck A, et al.: Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 2006, 439(7074):353-357.
• [5]Shedden K, Taylor JM, Enkemann SA, Tsao MS, Yeatman TJ, Gerald WL, Eschrich S, Jurisica I, Giordano TJ, Misek DE, et al.: Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med 2008, 14(8):822-827.
• [6]Lu TP, Tsai MH, Lee JM, Hsu CP, Chen PC, Lin CW, Shih JY, Yang PC, Hsiao CK, Lai LC, et al.: Identification of a novel biomarker, SEMA5A, for non-small cell lung carcinoma in nonsmoking women. Cancer Epidemiol Biomarkers Prev 2010, 19(10):2590-2597.
• [7]Lau SK, Boutros PC, Pintilie M, Blackhall FH, Zhu CQ, Strumpf D, Johnston MR, Darling G, Keshavjee S, Waddell TK, et al.: Three-gene prognostic classifier for early-stage non small-cell lung cancer. J Clin Oncol 2007, 25(35):5562-5569.
• [8]Kang J, D’Andrea AD, Kozono D: A DNA repair pathway-focused score for prediction of outcomes in ovarian cancer treated with platinum-based chemotherapy. J Natl Cancer Inst 2012, 104(9):670-681.
• [9]Lu TP, Lai LC, Tsai MH, Chen PC, Hsu CP, Lee JM, Hsiao CK, Chuang EY: Integrated analyses of copy number variations and gene expression in lung adenocarcinoma. PLoS One 2011, 6(9):e24829.
• [10]Bicaku E, Xiong Y, Marchion DC, Chon HS, Stickles XB, Chen N, Judson PL, Hakam A, Gonzalez-Bosquet J, Wenham RM, et al.: In vitro analysis of ovarian cancer response to cisplatin, carboplatin, and paclitaxel identifies common pathways that are also associated with overall patient survival. Br J Cancer 2012, 106(12):1967-1975.
• [11]Tsai CA, Chen JJ: Multivariate analysis of variance test for gene set analysis. Bioinformatics 2009, 25(7):897-903.
• [12]Sun YV: Integration of biological networks and pathways with genetic association studies. Hum Genet 2012, 131(10):1677-1686.
• [13]Tseng GC, Ghosh D, Feingold E: Comprehensive literature review and statistical considerations for microarray meta-analysis. Nucleic Acids Res 2012, 40(9):3785-3799.
• [14]Venet D, Dumont JE, Detours V: Most random gene expression signatures are significantly associated with breast cancer outcome. PLoS Comput Biol 2011, 7(10):e1002240.
• [15]Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehar J, Kryukov GV, Sonkin D, et al.: The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 2012, 483(7391):603-607.
• [16]Reungwetwattana T, Weroha SJ, Molina JR: Oncogenic pathways, molecularly targeted therapies, and highlighted clinical trials in non-small-cell lung cancer (NSCLC). Clin Lung Cancer 2012, 13(4):252-266.
• [17]Janku F, Garrido-Laguna I, Petruzelka LB, Stewart DJ, Kurzrock R: Novel therapeutic targets in non-small cell lung cancer. J Thorac Oncol 2011, 6(9):1601-1612.
• [18]Petrelli F, Borgonovo K, Cabiddu M, Barni S: Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials. Clin Lung Cancer 2012, 13(2):107-114.
• [19]Edgar R, Domrachev M, Lash AE: Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 2002, 30(1):207-210.
• [20]Furukawa C, Daigo Y, Ishikawa N, Kato T, Ito T, Tsuchiya E, Sone S, Nakamura Y: Plakophilin 3 oncogene as prognostic marker and therapeutic target for lung cancer. Cancer Res 2005, 65(16):7102-7110.
• [21]Lee ES, Son DS, Kim SH, Lee J, Jo J, Han J, Kim H, Lee HJ, Choi HY, Jung Y, et al.: Prediction of recurrence-free survival in postoperative non-small cell lung cancer patients by using an integrated model of clinical information and gene expression. Clin Cancer Res 2008, 14(22):7397-7404.
• [22]Raponi M, Zhang Y, Yu J, Chen G, Lee G, Taylor JM, Macdonald J, Thomas D, Moskaluk C, Wang Y, et al.: Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung. Cancer Res 2006, 66(15):7466-7472.
• [23]Matsuyama Y, Suzuki M, Arima C, Huang QM, Tomida S, Takeuchi T, Sugiyama R, Itoh Y, Yatabe Y, Goto H, et al.: Proteasomal non-catalytic subunit PSMD2 as a potential therapeutic target in association with various clinicopathologic features in lung adenocarcinomas. Mol Carcinog 2011, 50(4):301-309.
• [24]Kratz JR, He J, Van Den Eeden SK, Zhu ZH, Gao W, Pham PT, Mulvihill MS, Ziaei F, Zhang H, Su B, et al.: A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies. Lancet 2012, 379(9818):823-832.
• [25]Chen HY, Yu SL, Chen CH, Chang GC, Chen CY, Yuan A, Cheng CL, Wang CH, Terng HJ, Kao SF, et al.: A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med 2007, 356(1):11-20.
• [26]Zhu CQ, Ding K, Strumpf D, Weir BA, Meyerson M, Pennell N, Thomas RK, Naoki K, Ladd-Acosta C, Liu N, et al.: Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer. J Clin Oncol 2010, 28(29):4417-4424.
• [27]Chen DT, Hsu YL, Fulp WJ, Coppola D, Haura EB, Yeatman TJ, Cress WD: Prognostic and predictive value of a malignancy-risk gene signature in early-stage non-small cell lung cancer. J Natl Cancer Inst 2011, 103(24):1859-1870.
• [28]Wan YW, Beer DG, Guo NL: Signaling pathway-based identification of extensive prognostic gene signatures for lung adenocarcinoma. Lung Cancer 2012, 76(1):98-105.
• [29]Chiang YY, Chen SL, Hsiao YT, Huang CH, Lin TY, Chiang IP, Hsu WH, Chow KC: Nuclear expression of dynamin-related protein 1 in lung adenocarcinomas. Mod Pathol 2009, 22(9):1139-1150.
• [30]Beyer I, van Rensburg R, Strauss R, Li Z, Wang H, Persson J, Yumul R, Feng Q, Song H, Bartek J, et al.: Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer. Cancer Res 2011, 71(22):7080-7090.
• [31]Lu Y, Lemon W, Liu PY, Yi Y, Morrison C, Yang P, Sun Z, Szoke J, Gerald WL, Watson M, et al.: A gene expression signature predicts survival of patients with stage I non-small cell lung cancer. PLoS Med 2006, 3(12):e467.
• [32]Arioka H, Nishio K, Ishida T, Fukumoto H, Fukuoka K, Nomoto T, Kurokawa H, Yokote H, Abe S, Saijo N: Enhancement of cisplatin sensitivity in high mobility group 2 cDNA-transfected human lung cancer cells. Jpn J Cancer Res 1999, 90(1):108-115.
• [33]van der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D, Birrer MJ, Leaner VD: The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. Int J Cancer 2009, 124(8):1829-1840.
• [34]Sun S, Xu MZ, Poon RT, Day PJ, Luk JM: Circulating Lamin B1 (LMNB1) biomarker detects early stages of liver cancer in patients. J Proteome Res 2010, 9(1):70-78.
• [35]Pentheroudakis G, Batistatou A, Kalogeras KT, Kronenwett R, Wirtz RM, Bournakis E, Eleftheraki AG, Pectasides D, Bobos M, Papaspirou I, et al.: Prognostic utility of beta-tubulin isotype III and correlations with other molecular and clinicopathological variables in patients with early breast cancer: a translational Hellenic Cooperative Oncology Group (HeCOG) study. Breast Cancer Res Treat 2011, 127(1):179-193.
• [36]Chao YC, Pan SH, Yang SC, Yu SL, Che TF, Lin CW, Tsai MS, Chang GC, Wu CH, Wu YY, et al.: Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma. Am J Respir Crit Care Med 2009, 179(2):123-133.
• [37]Cho HJ, Baek KE, Kim IK, Park SM, Choi YL, Nam IK, Park SH, Im MJ, Yoo JM, Ryu KJ, et al.: Proteomics-based strategy to delineate the molecular mechanisms of RhoGDI2-induced metastasis and drug resistance in gastric cancer. J Proteome Res 2012, 11(4):2355-2364.
• [38]Selinger CI, Cooper WA, Al-Sohaily S, Mladenova DN, Pangon L, Kennedy CW, McCaughan BC, Stirzaker C, Kohonen-Corish MR: Loss of special AT-rich binding protein 1 expression is a marker of poor survival in lung cancer. J Thorac Oncol 2011, 6(7):1179-1189.
• [39]van de Vijver MJ, He YD, Van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, et al.: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002, 347(25):1999-2009.
• [40]Veer LJ V ‘t, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, Van der Kooy K, Marton MJ, Witteveen AT, et al.: Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002, 415(6871):530-536.
• [41]Chu CT, Sada YH, Kim ES: Vandetanib for the treatment of lung cancer. Expert Opin Investig Drugs 2012, 21(8):1211-1221.
• [42]Leboulleux S, Bastholt L, Krause T, de la Fouchardiere C, Tennvall J, Awada A, Gomez JM, Bonichon F, Leenhardt L, Soufflet C, et al.: Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol 2012, 13(9):897-905.
• [43]Wu X, Jin Y, Cui IH, Xu Z, Zhang Y, Zhang X, Tang C, Gong Y, Chen J: Addition of vandetanib to chemotherapy in advanced solid cancers: a meta-analysis. Anticancer Drugs 2012, 23(7):731-738.
• [44]Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, Katayama T, Kawashima S, Okuda S, Tokimatsu T, et al.: KEGG for linking genomes to life and the environment. Nucleic Acids Res 2008, 36:D480-D484.
• [45]Schaefer CF, Anthony K, Krupa S, Buchoff J, Day M, Hannay T, Buetow KH: PID: the Pathway Interaction Database. Nucleic Acids Res 2009, 37(Database issue):D674-D679.
• [46]Matthews L, Gopinath G, Gillespie M, Caudy M, Croft D, de Bono B, Garapati P, Hemish J, Hermjakob H, Jassal B, et al.: Reactome knowledgebase of human biological pathways and processes. Nucleic Acids Res 2009, 37(Database issue):D619-D622.
• [47]Cakir E, Yilmaz A, Demirag F, Oguztuzun S, Sahin S, Yazici UE, Aydin M: Prognostic significance of micropapillary pattern in lung adenocarcinoma and expression of apoptosis-related markers: caspase-3, bcl-2, and p53. APMIS 2011, 119(9):574-580.
• [48]Han SW, Roman J: Targeting apoptotic signaling pathways in human lung cancer. Curr Cancer Drug Targets 2010, 10(6):566-574.