Geographic and Viral Etiology Patterns of Promoter and Exon 3 Mutations in Hepatocellular Carcinoma: A Comprehensive Review.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. Genetic alterations play a critical role in hepatocarcinogenesis, with mutations in the telomerase reverse transcriptase promoter () and exon 3 representing two of the most frequently reported somatic events in HCC. However, the frequency and distribution of these mutations vary across geographic regions and viral etiologies, particularly hepatitis B virus (HBV) and hepatitis C virus (HCV). This study aimed to assess the global distribution and etiological associations of and exon 3 mutations in HCC through a comprehensive literature review. Our analysis, encompassing over 4000 HCC cases, revealed that mutations were present in 49.2% of tumors, with C228T being the predominant variant (93.3% among mutated cases). A striking contrast was observed between viral etiologies: mutations were detected in 31.6% of HBV-related HCCs, compared to 66.2% in HCV-related cases. exon 3 mutations were identified in 23.1% of HCCs, showing a similar association with viral etiology, being more common in HCV-related cases (30.7%) than in HBV-related tumors (12.8%). Geographically, both mutations exhibited comparable patterns, with higher frequencies in Europe, Japan, and the USA, while lower rates were observed in China, Taiwan, and South Korea. Our findings underscore the distinct molecular profiles of HCC according to viral etiology and geographic origin, highlighting the need for region- and etiology-specific approaches to HCC prevention, diagnosis, and targeted therapy.