Abstract 3821: A prognostic model of head and neck cancer ties TP53 mutation to 3p loss

Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by aggressive clinical behavior with a propensity for metastasis and recurrence. Current understanding of HNSCC pathogenesis remains limited, and there are few biomarkers that reliably predict patient outcomes such as survival or response to therapy. Here we report a comprehensive analysis of the molecular and clinical features of HNSCC that define patient survival. Building on data and infrastructure established by The Cancer Genome Atlas (TCGA), we develop an approach that integrates molecular events across multiple tiers of ‘omics data to progressively factor patients into subgroups with the greatest survival differences. We show that in HPV negative patients, the detrimental impact of TP53 mutation occurs only in combination with loss of chromosome 3p, leading to a marked decrease in median survival from >5 years for TP53 mutation only to 1.7 years for both events. Conditioned on TP53/3p, patients are stratified by a hierarchy of events incorporating MUC5B mutation, mir-548k expression, and mutation and expression of Abnormal Spindle Protein (ASPM), while in the absence of the TP53/3p event RAS signaling is an important driver. We also show in HPV positive patients that HPV-mediated inactivation of TP53 acts in synergy with 3p deletion. The major findings are replicated in an independent HNSCC cohort as well as a pan-cancer TCGA cohort of over 3000 patients. Together, the identified markers enable a new multi-tiered molecular classification of HNSCC. Citation Format: Andrew M. Gross, Ryan K. Orosco, John P. Shen, Ann Marie Egloff, Hannah Carter, Matan Hoffree, Michel Choueiri, Charles S. Coffey, Scott M. Lippman, David Neil Hayes, Ezra E. Cohen, Jennifer R. Grandis, Quyen T. Nguyen, Trey Ideker. A prognostic model of head and neck cancer ties TP53 mutation to 3p loss. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3821. doi:10.1158/1538-7445.AM2014-3821