Effects of EZH2 Polymorphisms on Susceptibility to and Pathological Development of Hepatocellular Carcinoma

Abstract

BackgroundThe enhancer of zeste 2 (EZH2) gene encodes the histone methyltransferase that is the catalytic component of the polycomb repressive complex-2, which initiates epigenetic silencing of genes. The expression level of EZH2 in hepatocellular carcinoma (HCC) is highly correlated with tumor progression; however, it has not been determined if specific EZH2 genetic variants are associated with the risk of HCC. This study investigated the potential associations of EZH2 single-nucleotide polymorphisms with HCC susceptibility and its clinicopathologic characteristics.Methodology/Principal FindingsA total of 220 HCC patients and 552 cancer-free controls were analyzed for four EZH2 single-nucleotide polymorphisms (rs6950683, rs2302427, rs3757441, and rs41277434) using real-time PCR genotyping. After adjusting for other co-variants, the individuals carrying at least one C allele at EZH2 rs6950683 and rs3757441 had a 0.611-fold and a 0.660-fold lower risk of developing HCC than did wild-type (TT) carriers, respectively. The CCCA or CCTA haplotype among the four EZH2 sites (rs6950683, rs2302427, rs3757441, and rs41277434), respectively, was also associated with a reduced risk of HCC. Furthermore, HCC patients who carried at least one C allele at rs6950683 or rs3757441 had a higher lymph–node-metastasis risk but a lower liver-cirrhosis risk than did patients carrying the wild-type allele.ConclusionsThe rs6950683 and rs3757441 polymorphic genotypes of EZH2 might contribute to the prediction of susceptibility to and pathological development of HCC. This is the first study to provide insight into risk factors associated with EZH2 variants in carcinogenesis of HCC in Taiwan.

Marginal zone lymphoma-derived interfollicular diffuse large B-cell lymphoma harboring 20q12 chromosomal deletion and missense mutation of BIRC3 gene: a case report

“…EZH2 is mutated in a variety of tumors including lymphomas and targeting of EZH2 protein with specific inhibitors show promising results in preclinical studies and early clinical trials [32–34]. Interestingly, it has been reported that EZH2 polymorphisms may contribute to susceptibility of tumor development and predict overall survival in some cancers [35–38] and may have also contributed to progression of the disease in this patient.…”

Mutant MMP-9 and HGF Gene Transfer Enhance Resolution of CCl4-Induced Liver Fibrosis in Rats: Role of ASH1 and EZH2 Methyltransferases Repression

“…EZH2 regulates cell proliferation and differentiation by silencing polycomb group target genes, and has been linked to the aggressiveness of human cancers, including hepatocellular carcinoma [30]. Moreover, EZH2 promotes epithelial–mesenchymal transition, a process that is associated with both liver carcinogenesis and injury and repair process [31].…”

EZH2 Single Nucleotide Variants (SNVs): Diagnostic and Prognostic Role in 10 Solid Tumor Types

“…The C alleles of rs6950683 and rs3757441 may predict a higher risk of developing lymph-node metastasis in HCC [26]. In two independent studies, we found that the C/C genotype at rs3757441 was significantly associated with shorter progression free survival (PFS) and overall survival (OS) (p < 0.01 and p < 0.05, respectively) in metastatic colorectal cancer (mCRC) patients [32,33].…”

“…The most studied EZH2 SNVs to potentially predict cancer susceptibility are rs6950683 and rs3757441; carrying the risk T alleles of either rs6950683 or rs3757441 reduces the risk (Odd Ratio: 0.7) of developing oral squamous cell carcinoma susceptibility (OSCC) [24] and particularly small-cell lung cancer (SCLC), when compared to non-small-cell lung cancer patients [25]. Patients carrying the protective C allele at rs3757441 and rs6950683 also showed lower risk of developing hepatocellular carcinoma (HCC) and urothelial carcinomas (UCC), respectively [26,27]. At odds with these studies, the rs3757441 C allele was significantly associated with higher risk of developing ESCC and with higher advanced pathological staging in these tumors [28].…”