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A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma
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Rare Germline Variants in Key Pathways Contribute to Hepatocellular Carcinoma Risk in Hispanic Individuals

Xiangnan Li1, Yanhong Liu1,2, Spiridon Tsavachidis1

  • 1Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

Cancers
|August 13, 2026
PubMed

Insights

Rare genetic variants in lipid metabolism and immune pathways significantly increase hepatocellular carcinoma (HCC) risk in Hispanic individuals. These findings help explain HCC disparities and guide future research in this population.

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.

Keywords:
Hispanicgenetic susceptibilityhepatocellular carcinomarare variant

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