Molecular Evolution of Genetic Susceptibility to Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a leading cancer-related cause of death worldwide. There are widespread global differences in HCC risk. Although the impact of geographic prevalence of specific causes of chronic liver disease on HCC is recognized, the contribution of the underlying genetic architecture to the risk of HCC remains undefined. Our aim was to characterize evolutionary trends in genetic susceptibility to HCC. We examined the genetic risk associated with HCC risk alleles identified from genome-wide association studies and correlated these with geographic location and temporal and spatial patterns of human migration. A moderate increase in differentiation was noted for rs2596542 (F (st) = 0.106) and rs17401966 (F (st) = 0.116), single nucleotide polymorphisms (SNPs) associated with an increased risk of HCC in patients with chronic HCV and HBV, respectively. Both of these SNPs show a recent increase in allelic frequency with the most recent human migrations into East Asia, Oceania and the Americas. In contrast another SNP associated with an increased risk of HCC, rs9275572, showed a lack of differentiation (F (st) = 0.09) with stable allelic expression across populations. The genetic risk score for HCC, based on the allelic frequency and risk odds ratio of five SNPs associated with increased risk of HCC, was greatest in populations from Africa and decreased with subsequent migration into Europe and Asia. However, a major increase was noted with the most recent migrations into Oceania and the Americas. There are differences in directional differentiation of HCC risk alleles across human populations that can contribute to population-based differences in HCC prevalence.