title: The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals.
abstract: Glutathione S-transferases (GSTs) detoxify toxic molecules by conjugation with reduced glutathione and regulate cell signaling. Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GSTA1 is expressed in hepatocytes and the rs3957357C>T (TT) SNP is known to downregulate GSTA1 mRNA expression, the aims of this study were: (i) to explore the relationship between the TT SNP in GSTA1 and the occurrence of HCC; (ii) to measure GSTA1 mRNA expression in HCCs. For that purpose, we genotyped non-tumor-tissue-derived DNA from 48 HCC patients and white-blood-cell-derived DNA from 37 healthy individuals by restriction fragment length polymorphism (RFLP). In addition, expression of GSTA1 mRNA was assessed by real-time PCR in 18 matching pairs of HCCs and non-tumor livers. Survival analysis was performed on an annotated microarray dataset containing 247 HCC patients (GSE14520). The GSTA1 TT genotype was more frequent in HCC than in non-HCC patients (27% versus 5%, respectively), suggesting that individuals carrying this genotype could be associated with 2-fold higher risk of developing HCCs (odds ratio = 2.1; p = 0.02). Also, we found that GSTA1 mRNA expression was lower in HCCs than in non-tumor livers. HCCs expressing the highest GSTA1 mRNA levels were the smallest in size (R = -0.67; p = 0.007), expressed the highest levels of liver-enriched genes such as ALB (albumin, R = -0.67; p = 0.007) and COL18A1 (procollagen type XVIII, R = -0.50; p = 0.03) and showed the most favorable disease-free (OR = 0.54; p<0.001) and overall (OR = 0.56; p = 0.006) outcomes. Moreover, GSTA1 was found within a 263-gene network involved in well-differentiated hepatocyte functions. In conclusion, HCCs are characterized by two GSTA1 features: the TT SNP and reduced GSTA1 gene expression in a context of hepatocyte de-differentiation.
authors.affiliation: Inserm, UMR991, Rennes, France.|Université de Rennes 1, Rennes, France.
authors.forename: Hanane
authors.initials: H
authors.lastname: Akhdar
authors.affiliation: Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon.|Inserm, UMR1122, Nancy, France.
authors.forename: Said
authors.initials: S
authors.lastname: El Shamieh
authors.affiliation: Inserm, UMR991, Rennes, France.|Université de Rennes 1, Rennes, France.
authors.forename: Orlando
authors.initials: O
authors.lastname: Musso
authors.affiliation: Inserm, UMR991, Rennes, France.|Université de Rennes 1, Rennes, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Désert
authors.affiliation: Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon.
authors.forename: Wissam
authors.initials: W
authors.lastname: Joumaa
authors.affiliation: Inserm, UMR991, Rennes, France.|Université de Rennes 1, Rennes, France.|CHU de Rennes, Service des Maladies du Foie, Rennes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Guyader
authors.affiliation: Inserm, UMR991, Rennes, France.|Université de Rennes 1, Rennes, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Aninat
authors.affiliation: Inserm, UMR991, Rennes, France.|Université de Rennes 1, Rennes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Corlu
authors.affiliation: Inserm, UMR991, Rennes, France.|Université de Rennes 1, Rennes, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Morel
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000208:ethnology / Q000235:genetics*; D005060:Europe; D020869:Gene Expression Profiling / Q000379:methods / Q000706:statistics & numerical data; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D063990:Gene Ontology; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000208:ethnology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: C484555:GSTA1 protein, human; D005982:Glutathione Transferase