P-171 - Genome-scale dissection of regulatory network dysfunction in tumors with high NRF2 activity

Abstract

NRF2 is a cytoprotective transcription factor, yet NRF2 hyperactivating mutations promote oncogenesis. We used an integrative genomics approach to get an unbiased view of gene dysregulation in tumors with oncogenic NRF2 mutations and identified a set of 32 direct NRF2 targets that are consistently upregulated in these tumors. This NRF2 cancer signature includes canonical redox-related NRF2 targets (e.g., NQO1) as well as several genes not previously linked to NRF2; upregulation of this gene set is independent of the organ where the tumor developed. A key distinguishing feature of the NRF2 cancer signature genes is that they are regulated by high affinity NRF2 binding sites (antioxidant response elements) that fall within DNA regions with a ubiquitously permissive chromatin signature. This implies that the NRF2 cancer target genes are broadly responsive to oncogenic NRF2 because they lack the epigenetic restraints that restrict expression of most NRF2 targets. We used this NRF2 cancer signature to infer NRF2 activity across 9000 tumors and found that high NRF2 activity is associated with decreased survival in many cancer types. Additionally, network-based screening for drivers of this universal NRF2 cancer signature has identified several novel genetic modifiers of NRF2 activity.