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

Area of Science:

• Genetics
• Hepatology
• Cancer Research

Background:

• Hepatocellular carcinoma (HCC) is a major global cause of cancer mortality.
• HCC incidence is highest in U.S. Hispanic populations, yet genetic risk factors, especially rare variants, remain understudied.
• Known genetic risk factors like PNPLA3 variants do not fully explain HCC disparities.

Purpose of the Study:

• To investigate rare germline genetic variants associated with HCC risk in Hispanic individuals.
• To identify specific genes and pathways contributing to HCC susceptibility in this demographic.
• To explore the relationship between genetic variants and clinical factors like liver disease etiology.

Main Methods:

• Whole-exome sequencing was performed on 719 Hispanic Americans (455 HCC cases, 264 controls).
• Analysis focused on rare to low-frequency, putatively deleterious variants in 86 HCC-associated genes.
• Statistical methods included single-variant tests, gene-based burden tests, and Fisher's exact tests.

Main Results:

• Twenty-nine rare deleterious variants in 16 genes were enriched in HCC cases.
• Significant associations were found in lipid metabolism (TM6SF2 R138W), immune regulation (HLA-DRB1 W38X), and Wnt signaling (WNT9A R357H).
• Carrying candidate variants increased HCC risk approximately 4-fold (OR, 3.84; 95% CI, 2.40-6.53), with a dose-effect relationship.

Conclusions:

• Rare deleterious germline variants in lipid metabolism and immune pathways are key contributors to HCC risk in Hispanic populations.
• These genetic findings offer a framework for understanding HCC health disparities.
• The study highlights the need for further mechanistic and epidemiological research in high-risk Hispanic populations.