Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features.
OBJECTIVE
To understand the role of nuclear factor erythroid-2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) in non-small cell lung cancer (NSCLC), we studied their expression in a large series of tumors with annotated clinicopathologic data, including response to platinum-based adjuvant chemotherapy.


METHODS
We determined the immunohistochemical expression of nuclear Nrf2 and cytoplasmic Keap1 in 304 NSCLCs and its association with patients' clinicopathologic characteristics, and in 89 tumors from patients who received neoadjuvant (n = 26) or adjuvant platinum-based chemotherapy (n = 63). We evaluated NFE2L2 and KEAP1 mutations in 31 tumor specimens.


RESULTS
We detected nuclear Nrf2 expression in 26% of NSCLCs; it was significantly more common in squamous cell carcinomas (38%) than in adenocarcinomas (18%; P < 0.0001). Low or absent Keap1 expression was detected in 56% of NSCLCs; it was significantly more common in adenocarcinomas (62%) than in squamous cell carcinomas (46%; P = 0.0057). In NSCLC, mutations of NFE2L2 and KEAP1 were very uncommon (2 of 29 and 1 of 31 cases, respectively). In multivariate analysis, Nrf2 expression was associated with worse overall survival [P = 0.0139; hazard ratio (HR), 1.75] in NSCLC patients, and low or absent Keap1 expression was associated with worse overall survival (P = 0.0181; HR, 2.09) in squamous cell carcinoma. In univariate analysis, nuclear Nrf2 expression was associated with worse recurrence-free survival in squamous cell carcinoma patients who received adjuvant treatment (P = 0.0410; HR, 3.37).


CONCLUSIONS
Increased expression of Nrf2 and decreased expression of Keap1 are common abnormalities in NSCLC and are associated with a poor outcome. Nuclear expression of Nrf2 in malignant lung cancer cells may play a role in resistance to platinum-based treatment in squamous cell carcinoma.
Solis
Luisa M
LM
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Behrens
Carmen
C
Dong
Wenli
W
Suraokar
Milind
M
Ozburn
Natalie C
NC
Moran
Cesar A
CA
Corvalan
Alejandro H
AH
Biswal
Shyam
S
Swisher
Stephen G
SG
Bekele
B Nebiyou
BN
Minna
John D
JD
Stewart
David J
DJ
Wistuba
Ignacio I
II
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D002466:Cell Nucleolus / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D012189:Retrospective Studies; D016896:Treatment Outcome
D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009944:Organoplatinum Compounds