Abstract
The p53 regulatory network responds to cellular stresses by initiating processes such as cell cycle arrest and apoptosis. These responses inhibit cellular transformation and mediate the response to many forms of cancer therapies. Functional variants in the genes comprising this network could help identify individuals at greater risk for cancer and patients with poorer responses to therapies, but few such variants have been identified as yet. We use the NCI60 human tumor cell line anticancer drug screen in a scan of single nucleotide polymorphisms (SNP) in 142 p53 stress response genes and identify 7 SNPs that exhibit allelic differences in cellular responses to a large panel of cytotoxic chemotherapeutic agents. The greatest differences are observed for SNPs in 14-3-3tau (YWHAQ; rs6734469, P=5.6x10(-47)) and CD44 (rs187115, P=8.1x10(-24)). In soft-tissue sarcoma patients, we find that the alleles of these SNPs that associate with weaker growth responses to chemotherapeutics associate with poorer overall survival (up to 2.89 relative risk, P=0.011) and an earlier age of diagnosis (up to 10.7 years earlier, P=0.002). Our findings define genetic markers in 14-3-3tau and CD44 that might improve the treatment and prognosis of soft-tissue sarcomas.
Highlights
The p53 protein plays a central role in eliciting cellular responses to a variety of stress signals and is crucial to an individual's ability to ward off cellular transformation and to respond to many forms of DNA damage–inducing cancer therapies [1, 2]
The genotypes for more than 100,000 single nucleotide polymorphisms (SNP) are publicly available for the NCI60 cell line panel and were determined using the Affymetrix 125K genotyping platform
Two hundred sixtyfour genotyped SNPs were found to reside in the 142 genes known to be important in the p53 stress response (Supplementary Table S1)
Summary
The p53 protein plays a central role in eliciting cellular responses to a variety of stress signals and is crucial to an individual's ability to ward off cellular transformation and to respond to many forms of DNA damage–inducing cancer therapies [1, 2]. A body of evidence is emerging in the literature that suggests that the inherited genetics of the p53 pathway could be used to further define patient populations in their abilities to respond to stress, suppress tumor formation, and induce p53 activity in response to DNA-damaging therapies [3, 4]. The common inherited genetic variations in the p53 pathway most frequently studied are single nucleo-.
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