Evolutionary action score of TP53 identifies high-risk mutations associated with decreased survival and increased distant metastases in head and neck cancer

David M. Neskey, Abdullah A. Osman, Thomas J. Ow, Panagiotis Katsonis, Thomas McDonald, Stephanie C. Hicks, Teng Kuei Hsu, Curtis R. Pickering, Alexandra Ward, Ameeta Patel, John S. Yordy, Heath D. Skinner, Uma Giri, Daisuke Sano, Michael D. Story, Beth M. Beadle, Adel K. El-Naggar, Merrill S. Kies, William N. William, Carlos CaulinMitchell Frederick, Marek Kimmel, Jeffrey N. Myers, Olivier Lichtarge

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

TP53 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 TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 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.

Original languageEnglish (US)
Pages (from-to)1527-1536
Number of pages10
JournalCancer research
Volume75
Issue number7
DOIs
StatePublished - Apr 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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