Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis

Abstract

Liver carcinogenesis is a complex and multi-factorial process, in which both environmental and genetic features interfere and contribute to malignant transformation. Patients with cirrhosis are particularly exposed and justify periodical screenings in order to detect the early development of hepatocellular carcinoma (HCC). The risk of HCC is, however, not identical from one patient to another. The identification of host factors that may also play an important role in HCC development may improve our understanding of the implications of the various biological pathways involved in liver carcinogenesis; such progress may as well help refine the selection of patients who could benefit from specific preventative measures or could be given adapted screening policies. Numerous candidate-gene studies have reported associations between single nucleotide polymorphisms (SNPs) and the presence of HCC. Some of these publications unfortunately suffer from major methodological drawbacks because of their case-control, retrospective and monocentric aspect. Prospective cohort studies conducted in large homogeneous populations and comprising a sufficient number of events during follow-up may overcome these pitfalls, but require a long time to be conducted and are still scarce. More recently, the first Genome Wide Association studies (GWAs) have enabled the identification of unsuspected loci that may be involved in various steps implicated in liver tumourigenesis. Taken together, these studies highlight variants that modulate oxidative stress, iron metabolism, inflammatory and immune responses, DNA repair mechanisms or systems involved in cell-cycle regulation as genetic traits susceptible to modify the natural history of cirrhotic patients and partly explain the observed differences in the risk of HCC occurrence. However, large genetic epidemiology studies in the field of cancer diseases have suggested the limited ability of polymorphic traits, alone, to refine individual prognosis. The integration of various panels of genes into clinical scores may in the near future define a "genomic risk prediction" specific to liver cancer developed in cirrhotic patients.

Independent and Additive Interaction Between Tumor Necrosis Factor β +252 Polymorphisms and Chronic Hepatitis B and C Virus Infection on Risk and Prognosis of Hepatocellular Carcinoma: a Case-Control Study

“…Aberrant expression of cytokines is thought to be critically involved (Haybaeck et al, 2009;Aggarwal et al, 2012;Nahon et al, 2012). TNFβ is oncogenic and acts as a tumor promoter (Aggarwal et al, 2012).…”

PNPLA3 gene in liver diseases

“…Therefore, a more rational approach will be the development of tailored predictive models integrating both clinical and genetic data that should be evaluated in prospective cohorts (Fig. 3) [120,121]. Data from prospective cohorts can be used to estimate positive and negative predictive values directly.…”

From Nonalcoholic Fatty Liver Disease to Hepatocellular Carcinoma: A Systems Understanding

“…It would also likely help fill the current gaps between conclusions derived from small-scale gene expression profiling studies and large-scale analysis of SNPs (single nucleotide polymorphisms) or GWAS. Nahon and Zucman-Rossi [10] reviewed the most robust and reliable published data regarding associations between genetic variants and the risk of HCC, including large-scale case-controlled studies, meta-analyses, prospective studies and GWAS. Despite limitations in combining studies with different methodological drawbacks, the review presents a comprehensive list of SNPs associated with the risk of HCC development.…”

“…can add confusion and interpretational variability. Short of performing a new meta-analysis based on publically available datasets, it is not easy to conclude whether the hepatic genes that were identified in the two discussed gene expression profiling studies [1,9] are congruent with SNPs associated with HCC [10]. Although the gene clusters associated with oxidative stress, iron metabolism, inflammatory and immune response, DNA repair, and cell cycle regulation pathways are considered the most likely to be involved in the progression to HCC, the contribution of individual genes to this sequence is not conclusive.…”

“…Although the gene clusters associated with oxidative stress, iron metabolism, inflammatory and immune response, DNA repair, and cell cycle regulation pathways are considered the most likely to be involved in the progression to HCC, the contribution of individual genes to this sequence is not conclusive. When SNPs curated from the NAFLD-related literature [3] were compared with those reviewed [10], common SNPs were identified in only four genes, from the Dig Dis Sci (2014) 59:238-241 239 oxidative stress response pathway (GSTM1 and SOD2), the inflammatory/immune response (TNF) and the previously mentioned PNPLA3 from lipid metabolism. Sample heterogeneity, however, was present, since variants associating with NAFLD were obtained from non-alcoholic patients whereas the HCC variants were obtained from studies comparing normal controls to hepatitis B or C (HBV or HCV)-infected patients or patients with a history of alcohol abuse.…”