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A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.

ABSTRACT: The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.

SUBMITTER: Zeron-Medina J

PROVIDER: S-EPMC4171736 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.

Zeron-Medina Jorge J Wang Xuting X Repapi Emmanouela E Campbell Michelle R MR Su Dan D Castro-Giner Francesc F Davies Benjamin B Peterse Elisabeth F P EF Sacilotto Natalia N Walker Graeme J GJ Terzian Tamara T Tomlinson Ian P IP Box Neil F NF Meinshausen Nicolai N De Val Sarah S Bell Douglas A DA Bond Gareth L GL

Cell 20131001 2

The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influenc ...[more]

PMID: 24120139

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Project description:BackgroundThis article presents a detailed analysis of a dataset consisting of 27 elements found in soils, soil eluates, and vegetables from private gardens in a region with a long history of coal mining and burning. With coal being one of the world's most significant energy sources, and previous studies highlighting elevated element levels in vegetables from this region, the objective of this study was to identify the factors that impact soil geochemistry and metal(loid) uptake in plants.MethodsTotal major and trace element concentrations were analyzed in soils, soil eluates and vegetables by high resolution inductively coupled plasma mass spectrometry. The vegetable samples included six species: fennel, garlic, lettuce, parsley, onion, and radicchio. Each plant was divided into roots, stems, leaves, and/or bulbs and analyzed separately. In addition, the soil pollution status, bioavailable fractions and transfer factors from soil and soil eluates to different plant parts were determined.ResultsThe comprehensive dataset revealed that, apart from the substrate enriched with various elements (Al, As, Co, Cr, Mo, Ni, Pb, Sb, Sn, Ti, U, V, and Zn), other anthropogenic factors such as the legacy of coal mining and combustion activities, associated industries in the area, transport, and agricultural practices, also influence the elevated element concentrations (Cd, Cu, Fe, Mn, and Se) in locally grown vegetables. The transfer factors based on element concentrations in aqueous soil eluates and element bioavailable fractions confirmed to be an effective tool for evaluating metal uptake in plants, emphazising to some extent the effects of plant species and revealing unique patterns for each pollution source within its environmental context (e.g., Cd, Mo, S, and Se in this case). The study highlights the crucial importance of utilizing comprehensive datasets that encompass a multitude of factors when interpreting the impacts of element uptake in edible plants.

Dataset Information

A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.

Publications

A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.

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