A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.
Cell
; 155(2): 410-22, 2013 Oct 10.
Article
em En
| MEDLINE
| ID: mdl-24120139
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Testiculares
/
Proteína Supressora de Tumor p53
/
Fator de Células-Tronco
/
Elementos de Resposta
/
Polimorfismo de Nucleotídeo Único
/
Estudo de Associação Genômica Ampla
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article