Evolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients

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 Evolut...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2015-04, Vol.75 (7), p.1205-1215
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Carcinoma, Squamous Cell - drug therapy
Carcinoma, Squamous Cell - genetics
Cell Line, Tumor
Cisplatin - pharmacology
Drug Resistance, Neoplasm
Female
Gene Expression
Humans
Male
Mice, Nude
Middle Aged
Mutation
Tongue Neoplasms - drug therapy
Tongue Neoplasms - genetics
Tumor Suppressor Protein p53 - genetics
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-14-2729