Multi-tiered genomic analysis of head and neck cancer ties TP53 mutation to 3p loss

Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive behavior with a propensity for metastasis and recurrence. Here we report a comprehensive analysis of the molecular and clinical features of HNSCC that govern patient survival. We find that TP53 mutation is frequently accompanied by loss of chromosome 3p and that the combination of these events is associated with a surprising decrease in survival time (1.9 years versus >5 years for TP53 mutation alone). The TP53-3p interaction is specific to chromosome 3p and validates in HNSCC and pan-cancer cohorts. In human papillomavirus (HPV)-positive tumors, in which HPV inactivates TP53, 3p deletion is also common and is associated with poor outcomes. The TP53-3p event is modified by mir-548k expression, which decreases survival further, and is mutually exclusive with mutations affecting RAS signaling. Together, the identified markers underscore the molecular heterogeneity of HNSCC and enable a new multi-tiered classification of this disease.

Figure 1. Prognostic effects and co-occurrence of TP53 and 3p

a, Five-year survival (error bars indicate 95% CI) for the most significant events of each category (colors). Numbers above bars represent number of patients with each event. b, Comparison of 5-year survival for patients with different types of non-silent TP53 mutations verses wild-type patients. L2 and L3 represent TP53 binding domains. Numbers in parentheses represent number of patients with a given mutation, patients with multiple TP53 mutations are represented multiple times in this plot. P-value represents log-rank test for TP53 mutation types excluding wild type. c, Hazard ratios for multivariate Cox model fit with 3p deletion and global deletion rate (CIN) across different patient sets (age covariate not shown, error bars indicate 95% CI, p-values represent significance of likelihood ratio test for model fit with and without 3p deletion). d, Venn diagram showing co-occurrence of TP53 mutation and deletions on the 3p chromosome. e, Kaplan-Meyer curves showing survival outcome for all combinations of 3p deletion and TP53 mutation events (colors correspond to patient subsets in panel d).

Figure 2. Replication of TP53-3p association

a, Survival comparison of patients with TP53-3p aggregate event versus those with only TP53 mutation in the independent UPMC cohort. b, Loss of 3p chromosomal arm is associated with lower survival in patients with HPV+ tumors (TCGA and independent cohorts). c, Assessment of 3p loss and TP53 mutation association in TCGA Pan-Cancer cohort (HNSCC excluded). d, Corresponding hazard ratio for multivariate model of three-year truncated survival (shown by dotted line in panel c) when controlling for tissue type, age, and stage covariates. Error bars indicate 95% confidence.

Figure 3. Characterization of molecular subtypes defined by the TP53-3p aggregate event

Patients with the TP53-3p aggregate event can be further stratified by the presence of a, mir-548k or b, MUC5B. c, Frequency of high gain amplification (top panel) and association with patient survival for gene / miRNA expression (bottom panel) along the 11q13 chromosomal segment. P-values in a and b are Benjamini-Hochberg-corrected for 1008 events a secondary prognostic biomarker screen (Methods). All survival associations are calculated by a likelihood ratio test with age and year of diagnosis used as covariates in the set of 179 patients with the TP53-3p event (TP53-3p negative curves shown for comparison, but not used in computation).