Rare Germline Variants in Key Pathways Contribute to Hepatocellular Carcinoma Risk in Hispanic Individuals

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. In the U.S., HCC incidence is highest among Hispanic populations. With the exception of well-known PNPLA3 variants, the genetic risk factors underlying HCC in Hispanic individuals, particularly rare germline variants, are largely unexplored. Methods: We performed whole-exome sequencing in 719 Hispanic Americans, including 455 HCC cases and 264 controls. We analyzed rare to low frequency, putatively deleterious variants in 86 genes previously implicated in HCC susceptibility. Genetic associations were assessed at single-variant, gene, and cumulative multi-variant burden levels using Fisher’s exact tests and weighted burden tests. Results: We identified 29 rare deleterious variants across 16 genes enriched in HCC cases compared with controls. Single-variant tests identified statistically robust associations in pathways related to lipids metabolism, TM6SF2 R138W, immune regulation, HLA-DRB1 W38X, and Wnt signaling pathway, WNT9A R375H. Exploratory analyses showed that TM6SF2 R138W was further enriched among cases with alcohol and metabolic dysfunction-associated steatotic liver disease. Gene-based burden tests revealed five associated genes, including TM6SF2 and HLA-DRB1. A strong dose-effect relationship was observed, with HCC risk increasing ~4-fold per candidate variant carried (odds ratio, 3.84; 95% confidence interval, 2.40–6.53). Conclusions: Rare deleterious germline variants across lipid metabolism and immune pathways contribute to increased HCC risk in Hispanic individuals. These findings provide a genetic framework for understanding HCC disparities and support future mechanistic and epidemiologic studies in this high-risk population.