Radiogenomic Analysis Demonstrates Associations between (18)F-Fluoro-2-Deoxyglucose PET, Prognosis, and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer.

Abstract

Purpose To investigate whether non-small cell lung cancer (NSCLC) tumors that express high normalized maximum standardized uptake value (SUVmax) are associated with a more epithelial-mesenchymal transition (EMT)-like phenotype. Materials and Methods In this institutional review board-approved study, a public NSCLC data set that contained fluorine 18 ((18)F) fluoro-2-deoxyglucose positron emission tomography (PET) and messenger RNA expression profile data (n = 26) was obtained, and patients were categorized on the basis of measured normalized SUVmax values. Significance analysis of microarrays was then used to create a radiogenomic signature. The prognostic ability of this signature was assessed in a second independent data set that consisted of clinical and messenger RNA expression data (n = 166). Signature concordance with EMT was evaluated by means of validation in a publicly available cell line data set. Finally, by establishing an in vitro EMT lung cancer cell line model, an attempt was made to substantiate the radiogenomic signature with quantitative polymerase chain reaction, and functional assays were performed, including Western blot, cell migration, glucose transporter, and hexokinase assays (paired t test), as well as pharmacologic assays against chemotherapeutic agents (half-maximal effective concentration). Results Differential expression analysis yielded a 14-gene radiogenomic signature (P < .05, false discovery rate [FDR] < 0.20), which was confirmed to have differences in disease-specific survival (log-rank test, P = .01). This signature also significantly overlapped with published EMT cell line gene expression data (P < .05, FDR < 0.20). Finally, an EMT cell line model was established, and cells that had undergone EMT differentially expressed this signature and had significantly different EMT protein expression (P < .05, FDR < 0.20), cell migration, glucose uptake, and hexokinase activity (paired t test, P < .05). Cells that had undergone EMT also had enhanced chemotherapeutic resistance, with a higher half-maximal effective concentration than that of cells that had not undergone EMT (P < .05). Conclusion Integrative radiogenomic analysis demonstrates an association between increased normalized (18)F fluoro-2-deoxyglucose PET SUVmax, outcome, and EMT in NSCLC. (©) RSNA, 2016 Online supplemental material is available for this article.