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TP53 R72P polymorphism modulates DNA methylation in hepatocellular carcinoma

Overview of attention for article published in Molecular Cancer, April 2015
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Title
TP53 R72P polymorphism modulates DNA methylation in hepatocellular carcinoma
Published in
Molecular Cancer, April 2015
DOI 10.1186/s12943-015-0340-2
Pubmed ID
Authors

Khadija Rebbani, Agnès Marchio, Sayeh Ezzikouri, Rajaa Afifi, Mostafa Kandil, Olfa Bahri, Henda Triki, Abdellah Essaid El Feydi, Anne Dejean, Soumaya Benjelloun, Pascal Pineau

Abstract

Hepatocellular 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. A 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. DNA 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). Our 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.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 41 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
France 1 2%
Unknown 40 98%

Demographic breakdown

Readers by professional status Count As %
Researcher 7 17%
Student > Ph. D. Student 7 17%
Student > Master 5 12%
Other 5 12%
Student > Doctoral Student 3 7%
Other 8 20%
Unknown 6 15%
Readers by discipline Count As %
Agricultural and Biological Sciences 8 20%
Medicine and Dentistry 7 17%
Biochemistry, Genetics and Molecular Biology 4 10%
Nursing and Health Professions 3 7%
Business, Management and Accounting 2 5%
Other 8 20%
Unknown 9 22%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 April 2015.
All research outputs
#7,172,905
of 8,294,943 outputs
Outputs from Molecular Cancer
#647
of 765 outputs
Outputs of similar age
#185,715
of 219,682 outputs
Outputs of similar age from Molecular Cancer
#42
of 45 outputs
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So far Altmetric has tracked 765 research outputs from this source. They receive a mean Attention Score of 3.2. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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We're also able to compare this research output to 45 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.