Transcriptomics Associates Molecular Features with 18F-Fluorocholine PET/CT Imaging Phenotype and Its Potential Relationship to Survival in Hepatocellular Carcinoma

Abstract

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-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 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.

Phospholipids are A Potentially Important Source of Tissue Biomarkers for Hepatocellular Carcinoma: Results of a Pilot Study Involving Targeted Metabolomics

“…We believe results from this comparison between classes of metabolites may be useful for prioritizing which metabolic pathways to pursue further for molecular imaging of HCC. Together with other information obtained from histopathologic, genomic, and transcriptomic analyses [16,17], this metabolomic data may help to inform the development of new imaging strategies for HCC. It is hoped that the success rate and utilization of non-histopathologic diagnostic algorithms will increase through the development of new tumor imaging modalities.…”

“…Beta-catenin activation has also been associated with increased fatty acid oxidation in HCC [48]. Imaging of lipid metabolism may therefore have the potential to discriminate specific molecular sub-types of HCC [17,44].…”

Addition of [18F]Fluorodeoxyglucose Positron Emission Tomography With Computed Tomography to Cross‐Sectional Imaging Improves Staging and Alters Management in Hepatocellular Carcinoma

“…( 8,9 ) For example, Kwee et al correlated high tumor [ 18 F]‐fluorocholine uptake with specific gene signatures and increased mortality. ( 23 ) Although prior studies have shown that PET‐CT positivity is associated with microvascular invasion and recurrence risk after surgical resection ( 9 ) and liver transplantation, ( 12 ) we did not have the sample size of patients in these subgroups to corroborate this finding.…”

Beta-catenin activation and immunotherapy resistance in hepatocellular carcinoma: mechanisms and biomarkers

“…Conversely, we found tumors displaying low FCH uptake were enriched by a T-cell inflammation signature that has been shown to be strongly predictive of clinical response to ICI therapy in several different cancers (FDR 0.116) [ Figure 3B] [15] . Furthermore, our previous published analysis of this radiogenomic dataset [54] reported that tumors displaying high FCH uptake disproportionately expressed gene signatures corresponding to distinct molecular classes of HCC, including the S3 class described by Hoshida et al [62] ; the G5 and G6 classes described by Boyault et al [63] ; and the "CTNNB1-activated" class described by Chiang et al [64] . All of these classes have more recently been associated with newly described immunotherapy-relevant HCC sub-types characterized by an immunosuppressed TME or poor ICI response as well as evidence of abnormal b-catenin activity [10,46,65] .…”