Genetic risk stratification reveals distinct first-order radiomic phenotypes in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) exhibits significant morphological heterogeneity that has traditionally been attributed to etiological, environmental, and biological factors. Recent evidence suggests, however, that genetic background may influence tumor characteristics and behavior in HCC.

To investigate associations between established HCC genetic risk factors and first-order radiomic features.

We evaluated a retrospective cohort of 210 patients with HCC who underwent contrast-enhanced MRI and genetic profiling for three established HCC risk variants (PNPLA3 rs738409-G, TM6SF2 rs58542926-T, and MAU2 rs58489806-T). We screened first-order radiomic features in the full cohort and then focused the primary analysis on 77 treatment-naive patients whose tumor morphology had not been modified by therapy. Patients were stratified into at-risk (≥1 risk allele, n=52) and wild-type (no risk alleles, n=25) groups. Eighteen first-order radiomic features were screened using the Mann-Whitney U test and AUC analysis. The leading feature, kurtosis, was then subjected to univariate and multivariate analysis for clinical and imaging features to identify any confounding effect. In addition, a 10-fold cross-validated cutpoint stability, sensitivity analysis, and Cox/Kaplan-Meier survival analysis were also conducted.

Among 18 features, kurtosis best distinguished at-risk from wild-type genotypes in treatment-naive patients (AUC = 0.67, p=0.014), with wild-type tumors showing more uniform, sharply peaked intensity patterns. Tumor volume correlated modestly with kurtosis (Spearman's ρ=0.45, p<0.0001), but volume alone did not discriminate genotype (Mann-Whitney U, p=0.3994). The genotype-kurtosis association remained significant after adjusting for volume and shape (ANCOVA, p=0.029) and strengthened after adjusting for nine clinical/demographic covariates (p=0.003), indicating kurtosis reflects biological information beyond tumor size. The empirical cutpoint was stable across 10-fold cross-validation (mean=3.35, SD = 0.05), and results were unchanged in sensitivity analysis. Kurtosis was not associated with overall survival (Cox HR = 1.19, p=0.13). No genotype-related discrimination was observed in the pooled full cohort, consistent with treatment-related alteration of tumor texture.

In a cohort of 210 genetically profiled patients with HCC, genotype-related radiomic features were not apparent when treated and untreated tumors were analyzed together. However, restricting the analysis to the treatment-naive subgroup (n=77) revealed tumor kurtosis as a reproducible, biologically plausible first-order imaging correlate of established HCC genetic risk status.