Aflatoxin exposure, chronic hepatitis infection, and HLA diversity converge to shape patient survival in hepatocellular carcinoma.

Aflatoxin remains an under-recognized hepatocellular‑carcinoma (HCC) risk factor in the United States, where the permissible food limit (20 ppb) is five‑fold higher than in Europe. We analyzed 350 TCGA-HCC cases with whole‑exome, RNA‑seq, and clinical data. Aflatoxin burden was quantified by single-base-substitution signature 24 (SBS24). HLA diversity was quantified from RNA‑seq reads using the Shannon diversity index. Multivariable Cox models estimated hazard ratios (HRs) for disease specific survival (DSS) with aflatoxin-virus interactions , adjusting for tumor stage, age, sex, race, alcohol use, fatty liver disease, aristolochic‑acid signature, and HLA diversity. Linear regression evaluated the association between HLA diversity and aflatoxin burden. Higher aflatoxin burden was associated with poorer DSS (aHR = 1.16, 95 % CI 1.01-1.33). Among HCV-positive patients, HBV infection was associated with improved DSS at low aflatoxin levels; however, this association was reversed at aflatoxin levels exceeding 30 units. HCV infection was consistently associated with worse DSS across aflatoxin levels. Asian American and Black/African American (AA) patients carried higher aflatoxin burdens than Whites (P = 0.016 and 0.014). Greater HLA diversity was independently associated with lower aflatoxin burden (P < 0.001), suggesting a protective effect. Somatic aflatoxin exposure, both independently and synergistically with HBV/HCV infection, adversely affects HCC prognosis, whereas greater HLA diversity may mitigate the detrimental effects of aflatoxin. Aflatoxin exposure disproportionately affected Asian-American and Black/AA patients (other minority groups not represented). Tightening U.S. aflatoxin food limits and expanding HBV vaccination coverage in high‑risk communities could reduce HCC disparities and improve patient survival.