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TP53 R72P polymorphism modulates DNA methylation in hepatocellular carcinoma
Khadija Rebbani1,2, Agnès Marchio3, Sayeh Ezzikouri4
1Unité d'Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, 28 rue du Docteur Roux, F-75724, Paris, Cedex 15, France. rebbanikhadija@gmail.com.
Molecular Cancer
|April 19, 2015
Summary
In low-incidence regions, TP53 Arg72Pro polymorphism drives hepatocellular carcinoma (HCC) epigenetic changes. This genotype may predict patient response to epigenetic therapies, offering new treatment strategies for HCC.
Area of Science:
- Oncology
- Epigenetics
- Genetics
Background:
- Hepatocellular carcinoma (HCC) exhibits significant epidemiological and molecular heterogeneity.
- In low-incidence regions like North Africa, HCC shows fewer mutations, suggesting a role for epigenetic alterations.
- This study investigated DNA methylation patterns in HCC from North African patients.
Purpose of the Study:
- To characterize DNA methylation in hepatocellular carcinoma (HCC) from North African patients.
- To explore the association between DNA methylation and TP53 Arg72Pro polymorphism in HCC.
- To evaluate the potential of TP53 genotype in predicting response to epigenetic therapy.
Main Methods:
- Analyzed DNA methylation at 11 tumor suppressor loci in 45 HCC specimens using methylation-specific PCR and combined-bisulfite restriction assay.
- Validated findings in liver cancer cell lines.
- Investigated the impact of TP53 codon 72 rs1042522 polymorphism on DNA methylation and drug response.
Main Results:
- DNA methylation was significantly higher in samples with chromosome instability.
- HCC patients with Arg/Arg genotype at TP53 codon 72 rs1042522 showed significantly higher DNA methylation (65%) compared to Pro/Pro carriers (20%).
- Arg72 p53 isoform re-methylated DNA faster, and Pro-carrying cell lines were more resistant to decitabine treatment.
Conclusions:
- The Arg72Pro polymorphism in a wild-type p53 context may drive epigenetic alterations in HCC.
- The rs1042522 genotype could predict sensitivity to epigenetic-targeted therapies for HCC.
- This model of liver tumorigenesis, linking genetic predisposition to epigenetic changes, may be relevant for populations in low-incidence areas.
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