Chemosensitivity Profiles Identify Polymorphisms in the p53 Network Genes 14-3-3t and CD44 That Affect Sarcoma Incidence and Survival

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 14-3-3 tau (YWHAQ; rs6734469, P = 5.6 x 10(-47)) and CD44 (rs187115, P = 8.1 x 10(-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 14-3-3 tau and CD44 that might improve the treatment and prognosis of soft-tissue sarcomas. Cancer Res; 70(1); 172-80. (C)2010 AACR.