Main insights of genome wide association studies into HCV-related HCC

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-mortality globally. Hepatocarcinogenesis is a complex multifactorial process. Host genetic background appeared to play a crucial role in the progression of HCC among chronic hepatitis C patients, especially in the era of Genome Wide Association Studies (GWAS) which allowed us to study the association of millions of single nucleotide polymorphisms (SNPs) with different complex diseases. This article aimed to review the discovered SNPs associated with the risk of HCVrelated HCC development which was reported in the published GWA studies and subsequent validation studies and also try to explain the possible functional pathways. Main text: We reviewed the recent GWA studies which reported several new loci associated with the risk of HCVrelated HCC, such as (SNPs) in MHC class I polypeptide-related sequence A (MICA), DEP domain-containing 5 (DEPDC5), Tolloid-like protein 1 (TLL1), and human leukocyte antigen (HLA) genes. We also explained the possible underlying biological mechanisms that affect the host immune response pathways. Additionally, we discussed the controversial results reported by the subsequent validation studies of different ethnicities. Conclusions: Although GWA studies reported strong evidence of the association between the identified SNPs and the risk of HCV-related HCC development, more functional experiments are necessary to confirm the defined roles of these genetic mutations for the future clinical application in different populations.

Correlation of DEPDC5 rs1012068 and rs5998152 Polymorphisms with Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

“…It may be that these polymorphisms weaken the activity of DEPDC5, preventing it from inhibiting mTORC1 as it does normally, which in turn leads to pathogenic inflammation and cell growth in the liver [ 22 , 29 ]. Future research should explore how the rs1012068 and rs5998152 polymorphisms affect DEPDC5 expression and activity.…”

Disheveled EGL-10 and pleckstrin domain-containing 5 rs1012068 T/G gene polymorphism among Egyptian chronic HCV-infected patients: disease progression and related complications

“…This was ascertained by another study which reported 40% increased risk of severe fibrosis with DEPDC5 rs1012068 T/G gene polymorphism. 15 Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury characterized by excessive accumulation of extracellular matrix proteins. 16 An in vitro study on immortalized hepatic stellate cells (HSCs) with high DEPDC5 expression was performed.…”

“…Accordingly, our findings can find its explanation based on researchers who reported that DEPDC5 gene pathogenic G variant is an inactivating variant leading to down-regulation of the encoded DEPDC5 protein. 15 Furthermore, down-regulation of the DEPDC5 protein caused by DEPDC5 gene polymorphism leads to decreasing its blocking effect on mTOR signaling pathway. 8,15 The consequent increased activity of the mTOR pathway promotes fibrosis through transforming growth factor-β (TGF-β) independent mechanism, 17 which is considered as another explanation of the molecular basis of genetic association of DEPDC5 variants with fibrosis progression.…”

“…15 Furthermore, down-regulation of the DEPDC5 protein caused by DEPDC5 gene polymorphism leads to decreasing its blocking effect on mTOR signaling pathway. 8,15 The consequent increased activity of the mTOR pathway promotes fibrosis through transforming growth factor-β (TGF-β) independent mechanism, 17 which is considered as another explanation of the molecular basis of genetic association of DEPDC5 variants with fibrosis progression. Fibrosis and distortion of hepatic architecture following endoplasmic reticulum stress, liver injury and inflammation is caused by HCV proteins particularly core and NS5A, 18,12 which was described to activate the mTOR signaling pathway induced by HCVinfected hepatocytes.…”

Host pharmacogenetic factors that may affect liver neoplasm incidence upon using direct-acting antivirals for treating hepatitis C infection

“…Regarding HCC as a consequence of HCV infection, host genetics also play an essential role. For example, the single-nucleotide polymorphisms (SNPs) rs2596542, rs1012068, rs17047200, and rs2856723 of the genes MICA , DEPDC5 , TLL1 , and HLA-DBQ1 , respectively, were found to be significantly associated with HCC development in patients with HCV [ 21 ].…”