Disruption of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex components by multiple genetic mechanisms: Association with poor prognosis in head and neck cancer.

BACKGROUND The NRF2 pathway has multiple pro-tumorigenic functions, and Nrf2 levels are increased in head and neck squamous cell carcinoma (HNSCC). The KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is a negative regulator of NRF2. In this study, we investigated mechanisms of disruption of individual complex components. METHODS Clinical and genomic profiles for 302 patients with HNSCC were obtained from The Cancer Genome Atlas. Combined pattern of epi/genetic alterations for individual components revealed frequent of complex disruption. Gene-set enrichment analysis was performed on expression data to identify affected pathways. RESULTS DNA loss is the main mechanism of alteration for all component genes, whereas hypermethylation largely affects only KEAP1. Combined analysis revealed that 64% of patients with HNSCC have disruption in this protein complex. Concordantly, NRF2-associated gene signature is enriched in HNSCC. Survival was significantly diminished among patients with one or more disrupted components. CONCLUSION The KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is frequently disrupted in HNSCC by multiple mechanisms. NRF2-based prognostics will benefit from integrated analysis of component genes.