RAPTOR protein overexpression is predictive of poor clinical outcomes in head and neck squamous cell carcinoma (HNSCC) patients

Abstract

Head and neck squamous cell carcinoma (HNSCC) has a high mortality rate, and with rising incidences in Asia. Previously, we demonstrated that the PI3K pathway is the most frequently altered pathway in HNSCC (Lui et al, Cancer Discovery, 2013). However, cumulative PI3K pathway aberrations, nor PIK3CA aberrations, are not associated with clinical outcomes in HNSCC patients (P=n.s.). In this study, we investigate the prognostic significance of RAPTOR (Regulatory associated protein of mTOR), a key component of the PI3K signaling pathway, in HNSCC. To examine the clinical relevance of RAPTOR levels in human cancers, including HNSCC, we performed pan-cancer analyses of RAPTOR protein levels in the Cancer Proteome Atlas datasets (TCPA, USA). Strikingly, across 28 tumor types examined, we found that RAPTOR protein overexpression is most significantly associated with poor patient survival in HNSCC (P=0.00162***), followed by renal clear cell carcinoma (P=0.00198), and stomach cancer (P=0.0443; Log-Rank test; Table 1). We then extracted the original quantification data of RAPTOR protein array of HNC (TCPA, USA), and performed RAPTOR expression-survival correlation analyses on quantitative basis by Kaplan-Meier analysis with Log-Rank test. We found that HNSCC patients with RAPTOR protein overexpression in their primary tumors (mean+5SEM) have significantly poorer overall survival (median OS=27.56 months) than patients with RAPTOR protein underexpression (mean-5SEM; median OS=68.43 months). Moreover, this group of RAPTOR-high patients are found to have a higher risk of recurrences, with an Odd Ratio of 1.75 (P=0.05; Fisher’s Exact test). Notably, this poor OS of RAPTOR-high HNSCC is much shorter than that of TP53-mutated HNSCC in the same cohort (45.8 months; TCGA Provisional,N=510). Further, patients with extreme-high levels of RAPTOR protein expression (top 5% cases) have an even worst OS of only 11.56 months vs 48.16 months (the remaining 95% cases). Using our small cohort of Asian HNSCC tumors as a validation cohort, we show that RAPTOR protein overexpression is very common in Asian HNSCC (37.5%; 6/16 cases), suggestive of its likely contribution to HNSCC in Asia as well. In conclusion, RAPTOR-high status is likely to be a useful predictive of very poor HNSCC patient survival, possibly superior than the previously known survival-related biomarker,TP53 mutation. RAPTOR is one of the first components of the PI3K pathway shown to be associated with patient outcome in HNSCC. Acknowledgements:VWYL receives fundings from Health and Medical Research Fund(#15160691), Research Grant Council, Hong Kong(GRF#1711484,#17121616,# 14168571;T12-401/13-R), UICP(UIM/329;Innovation and Technology Fund); Hong Kong Cancer Fund. YCL is supported by Postdoctoral Hub(UIM/329) from Innovation and Technology Fund, Hong Kong government.J YKC supported by Dr Stanley Ho Medical Foundation.