KEAP1 gene mutations and NRF2 activation are common in pulmonary papillary adenocarcinoma
Open accessAbstract
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.
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Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance.
“Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, thereby leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance (e.g., chemoresistance) (Figure 8) [161,162,163,164,165,166,167,168,169,170,171].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [170]
Aberrant Nrf2 expression and poor prognosis have been revealed in a wide range of cancers, including lung, esophageal, breast, bladder, liver, prostate, and colorectal carcinomas.
“numerous studies have revealed aberrant Nrf2 expression and poor prognosis in a wide range of cancers, including, among others, lung, esophageal, breast, bladder, liver, prostate, and colorectal carcinomas [161,162,169,170,171,173,174]”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [170]
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- Authors
- Li, Q. K., Singh, A., Biswal, S., Askin, F., & Gabrielson, E.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Li, Qing Kay
- Venue
- Journal of Human Genetics
- Published
- 2011-01-20
- Volume
- 56
- Issue
- 3
- Pages
- 230-234
- ISSN
- 1434-5161 (ISSN-L)
- 1435-232X
- PMC
- PMC3268659
- OpenAlex
- W2058493148
- Cited by
- 90
- References
- 22
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 11 · 2019: 8 · 2018: 9 · 2017: 7 · 2016: 9 · 2015: 8 · 2014: 10 · 2013: 6 · 2012: 6
- FWCI
- 6.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Flight Attendant Medical Research Institute
- National Cancer Institute (R01CA140492, P50CA058184)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- KEAP1 mutation, Nrf2 activation, p53 expression, ERCC1, RRM1, chemoresistance, prognosis
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Adenocarcinoma, Papillary, Base Sequence, DNA-Binding Proteins, Endonucleases, Humans, Lung Neoplasms, Mutation, Ribonucleoside Diphosphate Reductase, Transcriptional Activation, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2
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