Introduction: Assessment of host genetics by identification of single nucleotide polymorphisms (SNPs) has shown to play a crucial role in identifying individuals at a risk for hepatocellular carcinoma (HCC). A point mutation (G for T) in the signal transducer and activator of transcription 4 (STAT4) has been found to increase risk in hepatitis B virus (HBV)-associated HCC. However, most studies addressing its risk association have been performed in Asian populations
Methods: This is a cross-sectional study performed in Latin American and European individuals through our ESCALON network. We analyzed 270 HCC blood samples and 343 cirrhotic controls from Argentina, Chile, Colombia, Ecuador, Peru, and the Netherlands for the variant rs7574865 in STAT4. A mutation in the STAT4 was genotyped using TaqMan-genotyping assay. Chi-Squared and Fisher’s Exact test were used to evaluate the association between STAT4 and HCC.
Results: The median age for HCC in South Americans was 68 y/o (IQR 62-72) and in Europeans 67 y/o (IQR 61-71), with 61% and 75% being males, respectively. The proportions of individuals who developed HCC with a risk SNP (GG/GT) in the STAT4 gene was 85% in the Latin American cohort and 93% in the European one, as well as 85% and 96% respectively for cirrhotics without HCC. The calculated Odds-Ratio (OR) for HCC among Latin Americans with the G/G or G/T mutation in the STAT4 gene was 1.01 (CI 0.53-2.00, p=1) and among Europeans 0.71 (CI 0.16-2.55, p=0.78), suggesting and inverse association risk, but of low significance.
When evaluating HBV-related HCC specifically (11% of cases) we found OR of 2.20 (CI 0.16-23.00, p=0.58) in carriers of G mutation for the entire cohort, and OR of 3.00 (CI 0.1-90.96, p=1) for Latin Americans and OR of 2.35 (0.04-44.71, p=0.47) among Europeans. When comparing the TT genotype to GT and GG we found OR of 0.43 (CI 0.02-28.00, p=0.47) suggesting a protective effect in this population.
Discussion: STAT4 mutations do not seem to associate with HCC development in Latin American or European populations, likely due to a much higher prevalence of GG alleles than in Asians. In those with HBV-related HCC there seems to be an increased OR for presence of G mutation, but with a large CI (needing further verification). A larger study is ongoing to confirm these findings.
