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

Jorge Zeron-Medina; Xuting Wang; Emmanouela Repapi; Michelle R Campbell; Dan Su; Francesc Castro-Giner; Benjamin Davies; Elisabeth F P Peterse; Natalia Sacilotto; Graeme J Walker; Tamara Terzian; Ian P Tomlinson; Neil F Box; Nicolai Meinshausen; Sarah De Val; Douglas A Bell; Gareth L Bond

doi:10.1016/j.cell.2013.09.017

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

Jorge Zeron-Medina, Xuting Wang, Emmanouela Repapi, Michelle R Campbell, Dan Su, Francesc Castro-Giner, Benjamin Davies, Elisabeth F P Peterse, Natalia Sacilotto, Graeme J Walker, Tamara Terzian, Ian P Tomlinson, Neil F Box, Nicolai Meinshausen, Sarah De Val, Douglas A Bell, Gareth L Bond

Research output: Contribution to journal › Article › peer-review

93 Citations (Scopus)

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.

Original language	English
Pages (from-to)	410-22
Number of pages	13
Journal	Cell
Volume	155
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2013.09.017
Publication status	Published - 10 Oct 2013

Bibliographical note

Keywords

Animals
Cell Proliferation
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Mice
Polymorphism, Single Nucleotide
Response Elements
Selection, Genetic
Stem Cell Factor/genetics
Testicular Neoplasms/genetics
Transcription, Genetic
Tumor Suppressor Protein p53/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2013.09.017

Cite this

Zeron-Medina, J., Wang, X., Repapi, E., Campbell, M. R., Su, D., Castro-Giner, F., Davies, B., Peterse, E. F. P., Sacilotto, N., Walker, G. J., Terzian, T., Tomlinson, I. P., Box, N. F., Meinshausen, N., De Val, S., Bell, D. A., & Bond, G. L. (2013). A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection. Cell, 155(2), 410-22. https://doi.org/10.1016/j.cell.2013.09.017

@article{9bb002f7db964b1d9c345127e5aaefa7,

title = "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. ",

keywords = "Animals, Cell Proliferation, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mice, Polymorphism, Single Nucleotide, Response Elements, Selection, Genetic, Stem Cell Factor/genetics, Testicular Neoplasms/genetics, Transcription, Genetic, Tumor Suppressor Protein p53/metabolism",

author = "Jorge Zeron-Medina and Xuting Wang and Emmanouela Repapi and Campbell, {Michelle R} and Dan Su and Francesc Castro-Giner and Benjamin Davies and Peterse, {Elisabeth F P} and Natalia Sacilotto and Walker, {Graeme J} and Tamara Terzian and Tomlinson, {Ian P} and Box, {Neil F} and Nicolai Meinshausen and {De Val}, Sarah and Bell, {Douglas A} and Bond, {Gareth L}",

year = "2013",

month = oct,

day = "10",

doi = "10.1016/j.cell.2013.09.017",

language = "English",

volume = "155",

pages = "410--22",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier",

number = "2",

}

Zeron-Medina, J, Wang, X, Repapi, E, Campbell, MR, Su, D, Castro-Giner, F, Davies, B, Peterse, EFP, Sacilotto, N, Walker, GJ, Terzian, T, Tomlinson, IP, Box, NF, Meinshausen, N, De Val, S, Bell, DA & Bond, GL 2013, 'A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection', Cell, vol. 155, no. 2, pp. 410-22. https://doi.org/10.1016/j.cell.2013.09.017

TY - JOUR

T1 - A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection

AU - Zeron-Medina, Jorge

AU - Wang, Xuting

AU - Repapi, Emmanouela

AU - Campbell, Michelle R

AU - Su, Dan

AU - Castro-Giner, Francesc

AU - Davies, Benjamin

AU - Peterse, Elisabeth F P

AU - Sacilotto, Natalia

AU - Walker, Graeme J

AU - Terzian, Tamara

AU - Tomlinson, Ian P

AU - Box, Neil F

AU - Meinshausen, Nicolai

AU - De Val, Sarah

AU - Bell, Douglas A

AU - Bond, Gareth L

PY - 2013/10/10

Y1 - 2013/10/10

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Proliferation

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Mice

KW - Polymorphism, Single Nucleotide

KW - Response Elements

KW - Selection, Genetic

KW - Stem Cell Factor/genetics

KW - Testicular Neoplasms/genetics

KW - Transcription, Genetic

KW - Tumor Suppressor Protein p53/metabolism

U2 - 10.1016/j.cell.2013.09.017

DO - 10.1016/j.cell.2013.09.017

M3 - Article

C2 - 24120139

SN - 0092-8674

VL - 155

SP - 410

EP - 422

JO - Cell

JF - Cell

IS - 2

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this