KEAP1 gene mutations and NRF2 activation are common in pulmonary papillary adenocarcinoma.
Distinctive histological variants of lung cancer are increasingly recognized to have specific genetic changes that affect tumor biology and response to therapy. In this study, we evaluated true papillary adenocarcinoma of the lung, proposed as a distinct diagnostic category with relatively poor response to therapy, to determine whether these tumors also have specific molecular alterations that would affect sensitivity to chemotherapy. Specifically, we measured protein levels of P53, excision repair cross-complementation 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) by immunohistochemistry and evaluated the Kelch-like erythroid cell-derived protein with cap-n-collar homology (ECH)-associated protein 1 (KEAP1) gene for mutations, correlating mutations of this gene with total and nuclear expression of the nuclear factor erythroid-2-related factor 2 (NRF2). We found high levels of P53 in 23 of the 55 specimens (41.8%), similar to the rate of P53 gene mutations observed in general for pulmonary adenocarcinoma, and levels of ERCC1 and RRM1 also showed distributions similar to those reported generally for non-small lung cell cancer (NSCLC). However, KEAP1 alterations were observed at a significantly higher frequency in papillary adenocarcinoma tumors (60%) than what has been reported previously for NSCLC (3-19%). These mutations of KEAP1 were associated with increased nuclear accumulation of NRF2 in tumors, as expected for functional alterations. Thus, high rates of KEAP1 mutations and NRF2 overexpression in true papillary adenocarcinoma could be related to poor prognosis and chemotherapy resistance. Furthermore, this distinctive molecular characteristic supports the recognition of true papillary adenocarcinoma as a diagnostic entity.
Department of Pathology, The Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA. qli23@jhmi.edu
Qing Kay
QK
Li
Anju
A
Singh
Shyam
S
Biswal
Frederic
F
Askin
Edward
E
Gabrielson
D000231:Adenocarcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase; D015533:Transcriptional Activation / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; 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; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C071447:ERCC1 protein, human; D004720:Endonucleases
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