Elevated HLA-G Seen in HCC Driven by Viral Infections, Fatty Liver

New study findings are giving insight into the prognostic value of a certain gene in hepatocellular carcinoma (HCC) driven by viral infections or fatty liver.¹

The Italian study showed that patients with HCC resulting from viral infections or fatty liver had significantly higher levels of human leukocyte antigen G (HLA-G), which brought negative implications for survival. The researchers published their findings in Scientific Reports.

The sixth most common cancer and third leading cause of cancer-related death across the globe, HCC is often driven by viral infection such as hepatitis B virus (HBV)/hepatitis C virus (HCV) and fatty liver (steatotic liver disease [SLD]).²

“Although therapeutic advancements have been made, researchers are exploring new prognostic markers for early disease detection,” described the researchers of the new study.¹ “Recent genome-wide association studies (GWAS) reported that genetic polymorphisms in the HLA region may contribute significantly to the development of HCC.”

Approximately 35% of patients with low levels of the HLA-G were alive at 5 years, compared with 15% of patients with medium or high levels. | Image credit: Sebastian Kaulitzki - stock.adobe.com

Following 116 patients with HCC resulting from viral hepatitis and SLD, along with 140 healthy controls, the researchers found that levels of human leukocyte antigen G (HLA-G) were, on average, 3 to 4 times higher in patients with HCC, which was associated with worse survival.

Overall survival (OS) was significantly impacted by HLA-G levels, which the researchers noted were in line with studies of other malignancies suggesting that HCC cells evade immune surveillance by leveraging HLA-G expression.

The group observed that approximately 35% of patients with low levels (<25 U/mL) of the gene were alive at 5 years compared with 15% of patients with medium (25-80 U/mL) or high (>80 U/mL) levels. Median OS for patients with low levels of HLA-G was approximately 26.4 months vs 25.3 months for patients with medium levels vs 21.6 months for patients with high levels.

Compared with controls, patients with viral-related and SLD-related HCC had significantly elevated levels of HLA-G (Median [IQR], 31.70 (18.30) U/mL vs 14.50 (15.20) U/mL, respectively; P = 1.9 × 10-8, Pc = 0.003].

The vast majority (81.90%; n = 95) of patients with HCC in the study had viral hepatitis, including HCV (47.41%), HBV (27.59%), and both HBV and HCV (6.90%). The remaining 18.10% (n = 21) of patients had HCC resulting from SLD, which included SLD related to alcohol (71.4%) and metabolic dysfunction–associated SLD and metabolic dysfunction-associated steatohepatitis (28.6%).

Increased levels of HLA-G were seen for both HCV/HBV-related HCC (median [IQR], 31.70 (18.00) U/mL vs 14.50 (15.20) U/mL; HBV/HCV vs controls P < 0.0001, Pc = 0.013) and SLD-related (median [IQR], 53.30 (41.00) U/mL vs 14.50 (15.20) U/mL; SLD vs controls P = 0.00043, Pc = 0.008) HCC. While levels of the gene were higher among patients with SLD-related HCC than those with viral hepatitis-related HCC, the difference was not statistically significant (P < 0.05). The researchers noted that these findings are the first to characterize HLA-G levels in SLD-related HCC.

“The exact mechanism responsible for the rise in sHLA-G levels in these patients remains unclear; however, it is plausible that this increase serves as a countermeasure against the chronic low-grade inflammation driven by the high levels of proinflammatory cytokines associated with excess adipose tissue,” explained the researchers. “Similarly, overexpression of soluble HLA-G is a common feature in many inflammatory conditions, such as systemic lupus erythematosus, systemic sclerosis, and antiphospholipid syndrome.”

References

1. Mocci S, Perra A, Littera R, et al. Human leukocyte antigen-G in hepatocellular carcinoma driven by chronic viral hepatitis or steatotic liver disease. Sci Rep. Published online April 17, 2025. doi:10.1038/s41598-025-97406-4
2. Liver cancer causes, risk factors, and prevention. National Cancer Institute. Last updated May 15, 2024. Accessed April 24, 2025. https://www.cancer.gov/types/liver/what-is-liver-cancer/causes-risk-factors