title: Identification of gene signatures and molecular markers for human lung cancer prognosis using an in vitro lung carcinogenesis system.
abstract: 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.
authors.affiliation: Departments of Thoracic/Head and Neck MedicalOncology, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. rlotan@mdanderson.org
authors.forename: Humam
authors.initials: H
authors.lastname: Kadara
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.forename: Luisa
authors.initials: L
authors.lastname: Solis
authors.forename: Xuemin
authors.initials: X
authors.lastname: Gu
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Eiji
authors.initials: E
authors.lastname: Tahara
authors.forename: Dafna
authors.initials: D
authors.lastname: Lotan
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Reuben
authors.initials: R
authors.lastname: Lotan
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics / Q000302:isolation & purification; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes