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Evolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients
(AACR, 2015) Osman, Abdullah A.; Neskey, David M.; Katsonis, Panagiotis; Patel, Ameeta A.; Ward, Alexandra M.; Hsu, Teng-Kuei; Hicks, Stephanie C.; McDonald, Thomas O.; Ow, Thomas J.; Alves, Marcus Ortega; Pickering, Curtis R.; Skinner, Heath D.; Zhao, Mei; Sturgis, Eric M.; Kies, Merrill S.; El-Naggar, Adel; Perrone, Federica; Licitra, Lisa; Bossi, Paolo; Kimmel, Marek; Frederick, Mitchell J.; Lichtarge, Olivier; Myers, Jeffrey N.
TP53 is the most frequently altered gene in head and neck squamous cell carcinoma (HNSCC), with mutations occurring in over two thirds of cases; however, the predictive response of these mutations to cisplatin-based therapy remains elusive. In the current study, we evaluate the ability of the Evolutionary Action score of TP53-coding variants (EAp53) to predict the impact of TP53 mutations on response to chemotherapy. The EAp53 approach clearly identifies a subset of high-risk TP53 mutations associated with decreased sensitivity to cisplatin both in vitro and in vivo in preclinical models of HNSCC. Furthermore, EAp53 can predict response to treatment and, more importantly, a survival benefit for a subset of head and neck cancer patients treated with platinum-based therapy. Prospective evaluation of this novel scoring system should enable more precise treatment selection for patients with HNSCC.