Abstract
<div>Abstract<p><i>TP53</i> is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring <i>TP53</i> mutations as high or low risk, and validated this system in both <i>in vivo</i> and <i>in vitro</i> models. Patients with high-risk <i>TP53</i> mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk <i>TP53</i> mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations. <i>Cancer Res; 75(7); 1527–36. ©2015 AACR</i>.</p></div>
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