Phosphorylation of gH2AX as a novel prognostic biomarker for laryngoesophageal dysfunction-free survival.

María José De Miguel-Luken,Amancio Carnero,Vladimir Suarez,Manuel Chaves-Conde,Begoña Quintana,Jerónimo Pachón,David Chinchón,Verónica De Miguel-Luken,Isabel Tirado,Alicia Menoyo

doi:10.18632/oncotarget.9172

Abstract

Current larynx preservation treatments have achieved an improvement of laryngoesophageal dysfunction-free survival (LDS) but lead to significant toxicities and recurrences. At present, there is no evidence to select the group of patients that may benefit from preservation approaches instead of surgery. Therefore, laryngeal biomarkers could facilitate pretreatment identification of patients who could respond to chemoradiation-based therapy. In this study, we evaluated retrospectively 53 patients with larynx cancer to determine whether gH2AX phosphorylation (pH2AX) alone or in combination with the membrane protein MAP17 (PDZK1IP1) could be used as prognostic biomarkers. We also evaluated whether the completion of cisplatin treatment and radiotherapy could predict survival in combination with pH2AX.We found that the dose of cisplatin received but not the length of the radiotherapy influenced LDS. High-pH2AX expression was associated with prolonged LDS (HR 0.26, p = 0.02) while MAP17 correlated with overall survival (OS) (HR 0.98, p = 0.05). High-MAP17 and high-pH2AX combined analysis showed improved LDS (with 61.35 months vs 32.2 months, p = 0.05) and OS (with 66.6 months vs 39.8 months, p = 0.01). Furthermore, the subgroup of high-pH2AX and optimal dose of cisplatin was also associated with OS (72 months vs 38.6 months, p = 0.03) and LDS (66.9 months vs 27 months, p = 0.017). These findings suggest that pH2AX alone or better in combination with MAP17 may become a novel and valuable prognostic biomarker for patients with laryngeal carcinoma treated with preservation approaches.

Highlights

Squamous cell carcinoma of the head and neck represents 4% of all cancers diagnosed worldwide, with more than 500.000 new cases recorded in 2008 [1, 2]
We have shown that pH2AX has a prognostic role in patients with laryngeal cancer
Further research is needed, we think that our results are opening a new window to identify biomarkers that in the future may allow changes in clinical practice, as to date there are no biomarkers that could identify those patients that will benefit from radiotherapy-based treatments instead of surgery

Summary

Introduction

Squamous cell carcinoma of the head and neck represents 4% of all cancers diagnosed worldwide, with more than 500.000 new cases recorded in 2008 [1, 2]. The role of Human Papilomavirus (HPV) is well established for squamous cell carcinoma of the oropharynx but it remains unclear for laryngeal cancer [6]. These patients are at risk of developing second primary tumors due to chronic aerodigestive tract carcinogen exposure: 14% in 5 years, 26% in 10 years and www.impactjournals.com/oncotarget. The main prognostic factor for overall survival (OS) is tumor staging, where node invasion is more relevant than tumor extension [8]. Disease-free survival prognostic factors include PS [9, 13], node invasion [13, 14], localization [9], pathologic stage (pT) [14], surgical resection margins [13] and pretreatment tracheotomy [15]. T4 primary extension and more than 2 cm tumoral invasion of the base of the tongue were shown to be associated with increased salvage laryngectomy in the Veterans study [16]

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