Transcriptomics associates molecular features with 18F-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). PET/CT has also identified distinct molecular imaging subtypes, including those with increased and decreased choline metabolism as measured by tissue uptake of the radiopharmaceutical 18F-flurocholine. 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 18F-fluorocholine PET/CT followed by tumor resection and gene expression profiling. Over- and under- expressed components of previously published gene signatures were evaluated for enrichment between tumors with high and low 18F-fluorocholine uptake using gene set analysis. Significant gene sets were enumerated by false discovery rate (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 18F-fluorocholine uptake at FDR q < 0.05, including those from 3 different clinical molecular classification systems and 2 prognostic signatures for HCC that showed predictive value in the study cohort. Tumor avidity for 18F-fluorocholine was associated with favorable characteristics based on these signatures, with lower mortality based on survival analysis (hazard ratio 0.36, 95% confidence interval 0.14 to 0.95). Tumors demonstrating high 18F-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 18F-fluorocholine PET/CT as a molecular and prognostic classifier in HCC.

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