Radiogenomics deciphers tumor heterogeneity in hepatocellular carcinoma and combined hepatocellular-cholangiocarcinoma

BACKGROUND: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a highly heterogeneous cancer with limited knowledge of molecular features and prognosis. To compare the molecular features of cHCC-CCA with different subtypes of hepatocellular carcinoma (HCC) and to investigate the biological meanings of prognostic radiomic features in cHCC-CCA. METHODS: We performed an integrative analysis to investigate the heterogeneity of cHCC-CCA and HCC by combining transcriptomic and radiomic approaches. RNA sequencing revealed distinct transcriptomic profiles between cHCC-CCA and HCC. For radiomic analysis, an eight-feature radiomic signature was constructed using preoperative contrast-enhanced MRI to predict overall survival in cHCC-CCA, and its prognostic significance was validated in an external dataset. Furthermore, weighted gene co-expression network analysis was employed to correlate radiomic features with underlying biological pathways. RESULTS: LR-M subtype of cHCC-CCA exhibited more aggressive characteristics and immunosuppressive tumor microenvironment compared with LR-4/5 subtype, HCC with rim arterial-phase hyperenhancement (rim-APHE) and HCC without rim-APHE. The radiomic signature was correlated with overall survival (hazard ratio [HR], 5.47; 95% CI:2.08, 7.23, p = 0.006) in the cHCC-CCA validation cohort. Three types of prognostic radiomic features were correlated with distinct pathways: fatty acid metabolism, signaling pathways regulating pluripotency of stem cells and T cell receptor signaling pathway, respectively. Original_Glszm_GrayLevelNonUniformity might reflect the upregulation of fatty acid metabolism and immune suppression of cHCC-CCA. CONCLUSIONS: We illustrated the heterogeneity of subtypes of HCC and cHCC-CCA, which provides insights into the differentiation of primary liver cancer. Correlation of prognostic radiomic features with transcriptome profiles in cHCC-CCA enables noninvasive evaluation of tumor microenvironment.