Transcriptomics Associates Molecular Features with F-Fluorocholine PET/CT Imaging Phenotype and Its Potential Relationship to Survival in Hepatocellular Carcinoma.

Studies involving transcriptomics have revealed multiple molecular subtypes of hepatocellular carcinoma (HCC). Positron emission tomography/computed tomography (PET/CT) has also identified distinct molecular imaging subtypes, including those with increased and decreased choline metabolism as measured by the tissue uptake of the radiopharmaceutical F-fluorocholine. Gene signatures reflecting the molecular heterogeneity of HCC may identify the biological and clinical significance of these imaging subtypes. In this study, 41 patients underwent F-fluorocholine PET/CT, followed by tumor resection and gene expression profiling. Over- and underexpressed components of previously published gene signatures were evaluated for enrichment between tumors with high and low F-fluorocholine uptake using gene set analysis. Significant gene sets were enumerated by FDR based on phenotype permutation. Associations with overall survival were analyzed by univariate and multivariate proportional hazards regression. Ten gene sets related to HCC were significantly associated with high tumor F-fluorocholine uptake at FDR < 0.05, including those from three different clinical molecular classification systems and two prognostic signatures for HCC that showed predictive value in the study cohort. Tumor avidity for F-fluorocholine was associated with favorable characteristics based on these signatures with lower mortality based on survival analysis (HR 0.36; 95% confidence interval, 0.14-0.95). Tumors demonstrating high F-fluorocholine uptake were also enriched for genes involved in oxidative phosphorylation, fatty acid metabolism, peroxisome, bile acid metabolism, xenobiotic metabolism, and adipogenesis. These results provide a pathobiological framework to further evaluate F-fluorocholine PET/CT as a molecular and prognostic classifier in HCC. SIGNIFICANCE: A pathobiological framework for HCC brings together multiple prognostically relevant gene signatures via convergence with F-fluorocholine PET/CT imaging phenotype.