Abstract 1267
Background
NFE2L2 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.
Methods
We 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.
Results
We 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.
Conclusions
NFE2L2 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.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5939 - Matrix metalloproteinases and their tissue inhibitors genes abnormal DNA methylation in breast cancer
Presenter: Olga Simonova
Session: Poster Display session 1
Resources:
Abstract
2703 - Uveal melanoma cell lines depend on multiple signaling pathways for survival
Presenter: John Park
Session: Poster Display session 1
Resources:
Abstract
4849 - XAF1 and ZNF313 complex stimulates ER stress-induced apoptosis via direct GRP78 inhibition.
Presenter: Sungchan Jang
Session: Poster Display session 1
Resources:
Abstract
4801 - XAF1 assembles a destructive complex to induce BRCA1-mediated apoptosis via suppressing ERa and switching estrogen function
Presenter: Seung-hun Jang
Session: Poster Display session 1
Resources:
Abstract
3416 - Cancer associated fibroblasts promote cancer progression via Wnt2 secretion in colorectal cancer
Presenter: Hideaki Karasawa
Session: Poster Display session 1
Resources:
Abstract
4273 - Paired-related homeobox 1 overexpression promotes invasion and metastasis and is a prognostic factor for worse disease-free survival in patients with lung cancer
Presenter: Jung-jyh Hung
Session: Poster Display session 1
Resources:
Abstract
4241 - LncRNA-GC1 contributes to gastric cancer chemo-resistance through inhibition of miR-551b-3p and the overexpression of dysbindin
Presenter: Xin Guo
Session: Poster Display session 1
Resources:
Abstract
5388 - GLPG 1790, a new selective EPHA2 inhibitor, is active in colorectal cancer cell lines belonging to the CMS4/mesenchymal-like subtype
Presenter: Pietro Paolo Vitiello
Session: Poster Display session 1
Resources:
Abstract
5208 - Characterisation of growth hormone signal transduction in primary melanoma cell lines
Presenter: Karla Sousa
Session: Poster Display session 1
Resources:
Abstract
3156 - LAPTM5 protein can regulate TGF-β mediated MAPK and Smad signaling pathways in ovarian cancer cell
Presenter: Yan Gao
Session: Poster Display session 1
Resources:
Abstract