FAM72 Overexpression Linked to Aggressive Hepatocellular Carcinoma

A NEW bioinformatics study has identified the FAM72 gene family as a powerful prognostic marker in hepatocellular carcinoma (HCC), with high expression linked to more advanced disease and poorer survival.

Using The Cancer Genome Atlas (TCGA) and multiple external validation cohorts (ICGC and three GEO datasets), Kong and colleagues systematically analysed expression of FAM72A–D in liver cancer. All four genes were markedly upregulated in tumour tissue versus normal liver and were strongly associated with higher TNM stage, poorer histological grade, and worse overall prognosis. Diagnostic performance was high, with AUCs of 0.88–0.94 for distinguishing tumour from normal tissue.

Two-Gene FAM72 Score Outperforms Existing Models

The team went further to build a concise FAM72-based risk score. Mutations in FAM72A–D were common (up to 17%) and associated with reduced overall survival. A simple two-gene signature (FAM72A and FAM72D) robustly stratified patients into high- and low-risk groups across five independent cohorts, with time-dependent AUCs generally >0.63 and a concordance index superior to ten previously published multi-gene HCC prognostic models, despite using far fewer genes.

Single-cell RNA sequencing showed FAM72B–D were enriched in proliferating T cells, while FAM72A also appeared in myeloid and endothelial compartments, hinting at roles in both tumour cells and the immune microenvironment. High FAM72 expression and high FAM72 risk scores correlated with altered immune infiltration, including shifts in T-cell subsets and higher expression of immune checkpoints such as PDCD1, CD274, CTLA4, HAVCR2, ICOS, and TIGIT, features that could inform immunotherapy strategies.

Copy-number variation, rather than promoter methylation, emerged as the main driver of FAM72 overexpression. Pathway analyses linked the high-risk FAM72 signature to cell-cycle control, DNA repair, and MYC-related programmes, consistent with a role in tumour proliferation and genomic instability.

The authors conclude that FAM72A–D are promising diagnostic and prognostic biomarkers in HCC, and that the streamlined FAM72 risk score could support risk stratification and future immunotherapy decision-making.

Reference
Kong W et al. Systematic analysis of the expression profiles and prognostic values of the FAM72 family in liver cancer. Biochem Biophys Rep. 2025;DOI:10.1016/j.bbrep.2025.102358.