Human genetic variation and the risk of hepatocellular carcinoma development

Our understanding of the patho-physiology of hepatocellular carcinoma (HCC) is still much fragmented making difficult the improvement of the clinical outcome for the majority of HCC patients. Discovery of single nucleotide polymorphisms (SNPs) associated with individual susceptibility to HCC may enable the persons at risk to adapt their lifestyle and legitimate implementation by their doctors of surveillance programs facilitating early detection and subsequent management of the disease. To shed light on the influence of human genetic variation on HCC, we conducted a review of the meta-analyses of candidate SNPs and genome wide association studies (GWAS) performed for HCC by search of PubMed and Google Scholar databases. Genetic variations occurring in pathways historically considered as instrumental for liver tumorigenesis (TP53/MDM2, HLA, glutathione-S-transferases/cytochrome P540, TNFα/TGFβ, etc…) are discussed. An immense majority of the data has been produced in Eastern Asia (China, Japan, Korea). These meta-analyses indicate that the TP53, the MDM2 SNP309 G and the GSTT1 null genotype contribute to an increased risk of HCC both in Asians and Caucasians. Significant differences of odds ratios are, however, commonly observed between Eastern-Asians and other populations. Amazingly, GWAS studies performed so far exclusively with HCC patients from Eastern Asia produced drastically different outcomes pointing at unrelated biological pathways. The small magnitude of the risk associated with the genetic variants raises the question of their future utility as markers in clinical practice. An assessment of their impact on tumor progression (vascular invasion, metastases) remains, however, to be done and may prove to be more useful for clinicians. Finally, the evaluation of these variants is not available for various populations of the world and particularly for Subsaharan Africans who are especially affected by HCC.