Abstract
BackgroundHepatocellular carcinoma (HCC) is characterized by widespread epidemiological and molecular heterogeneity. Previous work showed that in the western part of North Africa, a region of low incidence of HCC, mutations are scarce for this tumor type. As epigenetic changes are considered possible surrogates to mutations in human cancers, we decided, thus, to characterize DNA methylation in HCC from North-African patients.MethodsA set of 11 loci was investigated in a series of 45 tumor specimens using methylation-specific and combined-bisulfite restriction assay PCR. Results obtained on clinical samples were subsequently validated in liver cancer cell lines.ResultsDNA methylation at tumor suppressor loci is significantly higher in samples displaying chromosome instability. More importantly, DNA methylation was significantly higher in Arg/Arg when compared to Pro/Pro genotype carriers at codon 72 rs1042522 of TP53 (65% vs 20% methylated loci, p = 0.0006), a polymorphism already known to affect somatic mutation rate in human carcinomas. In vitro experiments in cell lines indicated that enzymes controlling DNA methylation were differentially regulated by codon 72 Arg or Pro isoforms of p53. Furthermore, the Arg72-carrying version of p53 was shown to re-methylate DNA more rapidly than the pro-harboring isoform. Finally, Pro-carrying cell lines were shown to be significantly more resistant to decitabine treatment (two-fold, p = 0.005).ConclusionsOur data suggest that Arg72Pro polymorphism in a WT p53 context may act as a primary driver of epigenetic changes in HCC. It suggests, in addition, that rs1042522 genotype may predict sensitivity to epigenetic-targeted therapy. This model of liver tumorigenesis that associates low penetrance genetic predisposition to epigenetic changes emerges from a region of low HCC incidence and it may, therefore, apply essentially to population living in similar areas. Surveys on populations submitted to highly mutagenic conditions as perinatally-acquired chronic hepatitis B or aflatoxin B1 exposure remained to be conducted to validate our observations as a general model.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0340-2) contains supplementary material, which is available to authorized users.
Highlights
Hepatocellular carcinoma (HCC) is characterized by widespread epidemiological and molecular heterogeneity
Our data suggest that Arg72Pro polymorphism in a WT p53 context may act as a primary driver of epigenetic changes in HCC
In addition, that rs1042522 genotype may predict sensitivity to epigenetictargeted therapy. This model of liver tumorigenesis that associates low penetrance genetic predisposition to epigenetic changes emerges from a region of low HCC incidence and it may, apply essentially to population living in similar areas
Summary
Hepatocellular carcinoma (HCC) is characterized by widespread epidemiological and molecular heterogeneity. As epigenetic changes are considered possible surrogates to mutations in human cancers, we decided, to characterize DNA methylation in HCC from North-African patients. Hepatocellular carcinoma (HCC), the most frequent primary liver tumor, is a malignancy affecting around 7 105 patients each year, with highest incidences measured in Sub-Saharan Africa and Eastern Asia. Hypermethylation of a set of TSG such as RASSF1, RIZ, CDK2NA and GSTP1 is commonly reported in HCC [11]. Such targeted silencing is generally accompanied by a global hypomethylation affecting repetitive elements covering the genome [12,13]. The presence of an arginine at codon 72 is known to be associated with higher rates of somatic TP53 mutations in tumors [17]
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