Mutations in Keap1 are a potential prognostic factor in resected non‐small cell lung cancer

Abstract

Keap1 gene mutations are likely to be associated with a worse prognosis and lower postoperative disease-free survival rates in pathological Stage I-II NSCLC.

Role of Nrf2 in Oxidative Stress and Toxicity

“…Somatic mutations of NRF2 were often found in squamous cell carcinoma and were mostly located in ETGE (57%) and DLG (43%) motifs, both of which disrupt Keap1 DC-Nrf2 Neh2 binding (159,160). Mutations in KEAP1 were frequently associated with adenocarcinomas and were found in the DC (65%), IVR (29%), BTB (3%), and NTR (3%) domains, causing inhibition of Keap1 and stabilization of Nrf2 protein (161)(162)(163)(164). Lung and prostate tumors exhibit increased methylation of the KEAP1 promoter that downregulates KEAP1 expression (165).…”

Molecular Basis of Electrophilic and Oxidative Defense: Promises and Perils of Nrf2

“…Mutations of the KEAP1 gene in cancer involving missense mutations and amino acid substitutions can lead to impaired Keap1 function (Padmanabhan et al, 2006;Singh et al, 2006;Nioi and Nguyen, 2007;Ohta et al, NRF2 FUNCTION AND SIGNALING 2008;Shibata et al, 2008a;Takahashi et al, 2010). The mutations were mostly found in the DC domain (65%), followed by IVR (29%), BTB (3%), and the N-terminal region (3%), and were frequently associated with adenocarcinomas.…”

AberrantKeap1methylation in breast cancer and association with clinicopathological features

“…The highest frequency of mutations was found in gallbladder cancer (30.7%), ovarian clear cell carcinoma (29%) and NSCLC (19%). [6][7][8][13][14][15][16][17][18][19][20] Lower frequencies of mutations were demonstrated in endometrioid endometrial tumors (8.5%), non-clear cell ovarian cancer (8%), hepatocellular carcinoma (8.9%), colorectal cancer (7.8%), biliary duct carcinomas (5%), breast cancer (2%), prostate cancer (1.3%) and gastric cancer (1%). 13,17,21,22 However, immunohistochemical studies in lung cancer, endometrial tumors, renal and breast cancer demonstrated a high frequency of KEAP1 downregulation and/or Nrf2 overexpression in these tumor types, suggesting that the deregulation of KEAP1 may play a role in carcinogenesis beside the presence of genomic alterations.…”