2034P - Genetic landscape of KEAP1 and NFE2L2 mutated cancers from the AACR GENIE database

Abstract

BackgroundNFE2L2 encodes Nrf2, which is activated at times of cellular stress to neutralize reactive oxygen species. KEAP1 acts as a negative regulator of Nrf2. Nrf2 has been implicated in tumorigenesis of many human cancers via the mTOR pathway. The prevalence and genetic landscape of NFE2L2 and KEAP1 mutants remains poorly characterized. MethodsWe extracted data from AACR GENIE 5.0 database, including only subjects with complete demographic, mutational, and CNA data (n=54,237). We quantified the prevalence of NFE2L2 and KEAP1 mutations, determined location frequency by gene subdomain, copy number alterations, and most frequent co-mutated genes. ResultsWe identified 720 NFE2L2 mutations and 1422 KEAP1 mutations. NFE2L2-mutated samples showed a difference in age (61.6 vs 55.9 years, p<.01) but had no gender difference (48.9% vs 49.1% female, p=0.8). NFE2L2 was most commonly mutated in head and neck (6.0%), anal (5.1%), and endometrial (4.5%) cancer samples. 391 (54.3%) mutations were seen in the Neh2 binding domain. TP53(51%), KMT2D(29.4%), and PIK3CA(26.4%) were most commonly co-mutated. KEAP1-mutated samples showed no difference in age (58.3 vs 59.0 years, p=0.75) nor gender (40.2% vs 48.4% female, p=0.31). KEAP1 mutations were most common in non-small cell lung (9.4%), unknown primary (6.9%), and small cell lung (4.0%) cancers. 696 (48.9%) mutations were seen in the KELCH binding domain. TP53 (53.8%), STK11(35.0%), and KRAS (30.9%) were the most common co-mutations. Based on prevalence identified in this study and publicly available epidemiological data, we estimate an annual incidence of nearly 60,000 cancers with NFE2L2 or KEAP1 mutations in the United States alone. ConclusionsNFE2L2 and KEAP1 mutations in their respective binding domains were found in a wide variety of cancer types. Based on estimated incidence of these mutations, mTOR inhibitors may play an important role in treating a signficant number of cancers. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.