Shaping Genetic Alterations in Human Cancer: The p53 Mutation Paradigm

Université P.M. Curie, 4 place Jussieu, 75005 Paris, France.
Cancer Cell (Impact Factor: 23.89). 11/2007; 12(4):303-12. DOI: 10.1016/j.ccr.2007.10.001
Source: PubMed

ABSTRACT p53 mutations are found in 50% of human cancers. Molecular epidemiology has shown strong correlations between the spectrum of p53 mutations and exposure to exogenous carcinogens. This spectrum is influenced quantitatively and qualitatively by various upstream genetic filters that modulate carcinogen activation, detoxification, and/or DNA repair. In this review, we will discuss how other factors such as tissue specificity, SNP of genes associated with the p53 pathway, other genetic alterations, or p53 mutant heterogeneity can act as a second set of downstream filters that also have a profound impact on the spectrum of p53 mutations.

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    ABSTRACT: Background 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. Methods 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. Results 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). Conclusions 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. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0340-2) contains supplementary material, which is available to authorized users.
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    ABSTRACT: Bitkilerdeki fenotipik varyasyonların birçoğunun kaynağını genlerdeki nükleotid dizin polimorfizmi oluşturmaktadır. Bu şekilde varyasyonlar, DNA analizine yönelik çeşitli markör tekniklerle (RFLP, CAPs, SSR, AFLP vb.) ortaya konulabilmektedir. Ancak fenotipik varyasyonun ana kaynağını oluşturan, genlerdeki birçok mutasyon şekilleri (nükleotidlerde eklenme, kayıplar, tek nükleotid bazında değişimler) bu yöntemlerle etkin bir şekilde tanımlanamamaktadır. SSCP tekniği orijinal olarak mutasyonların hızlı analizi için geliştirilmiştir. Mutasyonların analizinde; “SSCP (single strand conformation polymorphism)” markörler oldukça hassas ve doğru sonuçlar vermesi nedeniyle avantaj sağlamaktadır. Özellikle son yıllarda genetik çalışmalarda mutasyon, farklı bir yönde ele alınmaya başlanmıştır. Genomda mutasyona uğrayan bölgelerin moleküler olarak belirlenmesi bitkisel araştırmalarda önemli yer tutmaktadır. Yapılan çalışmalarla bitkilerde mutasyonların mekanizması anlaşılmaya çalışılmıştır.

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