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DOI: 10.1055/s-0044-1786004
Prevalence and Associations of Co-occurrence of NFE2L2 Mutations and Chromosome 3q26 Amplification in Lung Cancer
Funding This study was funded by the National Key R&D Program of China (grant number: 2021YFC2500900).![](https://www.thieme-connect.de/media/10.1055-s-00046370/202402/lookinside/thumbnails/10-1055-s-0044-1786004_2400018-1.jpg)
Abstract
Background NFE2L2 (nuclear factor erythroid-2-related factor-2) encodes a basic leucine zipper (bZIP) transcription factor and exhibits variations in various tumor types, including lung cancer. In this study, we comprehensively investigated the impact of simultaneous mutations on the survival of NFE2L2-mutant lung cancer patients within specific subgroups.
Methods A cohort of 1,103 lung cancer patients was analyzed using hybridization capture-based next-generation sequencing.
Results The NFE2L2 gene had alterations in 3.0% (33/1,103) of lung cancer samples, including 1.5% (15/992) in adenocarcinoma and 16.2% (18/111) in squamous cell carcinoma. Thirty-four variations were found, mainly in exons 2 (27/34). New variations in exon 2 (p.D21H, p.V36_E45del, p.F37_E45del, p.R42P, p.E67Q, and p.L76_E78delinsQ) were identified. Some patients had copy number amplifications. Co-occurrence with TP53 (84.8%), CDKN2A (33.3%), KMT2B (33.3%), LRP1B (33.3%), and PIK3CA (27.3%) mutations was common. Variations of NFE2L2 displayed the tightest co-occurrence with IRF2, TERC, ATR, ZMAT3, and SOX2 (p < 0.001). In The Cancer Genome Atlas Pulmonary Squamous Carcinoma project, patients with NFE2L2 variations and 3q26 amplification had longer median survival (63.59 vs. 32.04 months, p = 0.0459) and better overall survival.
Conclusions NFE2L2 mutations display notable heterogeneity in lung cancer. The coexistence of NFE2L2 mutations and 3q26 amplification warrants in-depth exploration of their potential clinical implications and treatment approaches for affected patients.
Keywords
NFE2L2 - lung cancer - 3q36 amplification - co-occurrence mutations - next-generation sequencingAvailability of Data and Materials
The majority of data presented in the study are included in the article; further inquiries can be directed to the corresponding author.
Authors' Contributions
J.L. contributed to data curation. S.L., D.L., and F.Z. helped in investigation. H.L. and F.Z. helped in writing—review, editing, and resources. S.L., H.L., and F.Z. helped in supervision. J.L. contributed to visualization and writing—original draft. All authors have read and agreed to the published version of the manuscript.
Publikationsverlauf
Artikel online veröffentlicht:
15. April 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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References
- 1 Cuadrado A, Manda G, Hassan A. et al. Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach. Pharmacol Rev 2018; 70 (02) 348-383
- 2 Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489 (7417) 519-525
- 3 DeBlasi JM, DeNicola GM. Dissecting the crosstalk between NRF2 signaling and metabolic processes in cancer. Cancers (Basel) 2020; 12 (10) 3023
- 4 Kitamura H, Motohashi H. NRF2 addiction in cancer cells. Cancer Sci 2018; 109 (04) 900-911
- 5 Colburn NH, Kensler TW. Targeting transcription factors for cancer prevention–the case of Nrf2. Cancer Prev Res (Phila) 2008; 1 (03) 153-155
- 6 Singh A, Misra V, Thimmulappa RK. et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med 2006; 3 (10) e420
- 7 Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M. Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res 2013; 73 (13) 4158-4168
- 8 Yang H, Wang W, Zhang Y. et al. The role of NF-E2-related factor 2 in predicting chemoresistance and prognosis in advanced non-small-cell lung cancer. Clin Lung Cancer 2011; 12 (03) 166-171
- 9 Binkley MS, Jeon YJ, Nesselbush M. et al. KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer Discov 2020; 10 (12) 1826-1841
- 10 Frank R, Scheffler M, Merkelbach-Bruse S. et al. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clin Cancer Res 2018; 24 (13) 3087-3096
- 11 Barrera-Rodríguez R. Importance of the Keap1-Nrf2 pathway in NSCLC: is it a possible biomarker?. Biomed Rep 2018; 9 (05) 375-382
- 12 Goldstein LD, Lee J, Gnad F. et al. Recurrent loss of NFE2L2 exon 2 is a mechanism for Nrf2 pathway activation in human cancers. Cell Rep 2016; 16 (10) 2605-2617
- 13 DeNicola GM, Karreth FA, Humpton TJ. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011; 475 (7354) 106-109
- 14 Bauer AK, Hill III T, Alexander CM. The involvement of NRF2 in lung cancer. Oxid Med Cell Longev 2013; 2013: 746432
- 15 Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell 2018; 34 (01) 21-43
- 16 Xu X, Yang Y, Liu X. et al. NFE2L2/KEAP1 mutations correlate with higher tumor mutational burden value/PD-L1 expression and potentiate improved clinical outcome with immunotherapy. Oncologist 2020; 25 (06) e955-e963
- 17 Marinelli D, Mazzotta M, Scalera S. et al. KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden. Ann Oncol 2020; 31 (12) 1746-1754
- 18 Massion PP, Kuo WL, Stokoe D. et al. Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway. Cancer Res 2002; 62 (13) 3636-3640
- 19 Kawano O, Sasaki H, Endo K. et al. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 2006; 54 (02) 209-215
- 20 Okudela K, Suzuki M, Kageyama S. et al. PIK3CA mutation and amplification in human lung cancer. Pathol Int 2007; 57 (10) 664-671
- 21 Ji M, Guan H, Gao C, Shi B, Hou P. Highly frequent promoter methylation and PIK3CA amplification in non-small cell lung cancer (NSCLC). BMC Cancer 2011; 11: 147
- 22 Karakas B, Bachman KE, Park BH. Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 2006; 94 (04) 455-459
- 23 Mitsuishi Y, Taguchi K, Kawatani Y. et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 2012; 22 (01) 66-79
- 24 Abazeed ME, Adams DJ, Hurov KE. et al. Integrative radiogenomic profiling of squamous cell lung cancer. Cancer Res 2013; 73 (20) 6289-6298
- 25 Chen X, Wu Q, Chen Y. et al. Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of paclitaxel in non-small cell lung cancer cells via Nrf2 inhibition. Br J Pharmacol 2019; 176 (12) 2079-2094
- 26 Goeman F, De Nicola F, Scalera S. et al. Mutations in the KEAP1-NFE2L2 pathway define a molecular subset of rapidly progressing lung adenocarcinoma. J Thorac Oncol 2019; 14 (11) 1924-1934
- 27 Sun X, Wang Y, Ji K. et al. NRF2 preserves genomic integrity by facilitating ATR activation and G2 cell cycle arrest. Nucleic Acids Res 2020; 48 (16) 9109-9123
- 28 van de Haar J, Canisius S, Yu MK, Voest EE, Wessels LFA, Ideker T. Identifying epistasis in cancer genomes: a delicate affair. Cell 2019; 177 (06) 1375-1383
- 29 Canale M, Petracci E, Delmonte A. et al. Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors. Clin Cancer Res 2017; 23 (09) 2195-2202
- 30 Pao W, Wang TY, Riely GJ. et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005; 2 (01) e17
- 31 Marchetti A, Martella C, Felicioni L. et al. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 2005; 23 (04) 857-865
- 32 Zhang C, Wang K, Lin J, Wang H. Non-small-cell lung cancer patients harboring TP53/KRAS co-mutation could benefit from a PD-L1 inhibitor. Future Oncol 2022; 18 (27) 3031-3041
- 33 Gu M, Xu T, Chang P. KRAS/LKB1 and KRAS/TP53 co-mutations create divergent immune signatures in lung adenocarcinomas. Ther Adv Med Oncol 2021; 13: 17 588359211006950
- 34 Skoulidis F, Goldberg ME, Greenawalt DM. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 2018; 8 (07) 822-835
- 35 Sasaki H, Suzuki A, Shitara M. et al. Genotype analysis of the NRF2 gene mutation in lung cancer. Int J Mol Med 2013; 31 (05) 1135-1138
- 36 Kerins MJ, Ooi A. A catalogue of somatic NRF2 gain-of-function mutations in cancer. Sci Rep 2018; 8 (01) 12846
- 37 Inoue D, Suzuki T, Mitsuishi Y. et al. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma. Cancer Sci 2012; 103 (04) 760-766
- 38 Campbell JD, Alexandrov A, Kim J. et al; Cancer Genome Atlas Research Network. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet 2016; 48 (06) 607-616
- 39 Klein MI, Cannataro VL, Townsend JP, Newman S, Stern DF, Zhao H. Identifying modules of cooperating cancer drivers. Mol Syst Biol 2021; 17 (03) e9810
- 40 Speicher MR, Howe C, Crotty P, du Manoir S, Costa J, Ward DC. Comparative genomic hybridization detects novel deletions and amplifications in head and neck squamous cell carcinomas. Cancer Res 1995; 55 (05) 1010-1013
- 41 Pelosi G, Del Curto B, Trubia M. et al. 3q26 Amplification and polysomy of chromosome 3 in squamous cell lesions of the lung: a fluorescence in situ hybridization study. Clin Cancer Res 2007; 13 (07) 1995-2004
- 42 Heselmeyer K, Schröck E, du Manoir S. et al. Gain of chromosome 3q defines the transition from severe dysplasia to invasive carcinoma of the uterine cervix. Proc Natl Acad Sci U S A 1996; 93 (01) 479-484
- 43 Singh B, Stoffel A, Gogineni S. et al. Amplification of the 3q26.3 locus is associated with progression to invasive cancer and is a negative prognostic factor in head and neck squamous cell carcinomas. Am J Pathol 2002; 161 (02) 365-371
- 44 Chen S, Li X, Lu D. et al. SOX2 regulates apoptosis through MAP4K4-survivin signaling pathway in human lung cancer cells. Carcinogenesis 2014; 35 (03) 613-623
- 45 Lee SH, Oh SY, Do SI. et al. SOX2 regulates self-renewal and tumorigenicity of stem-like cells of head and neck squamous cell carcinoma. Br J Cancer 2014; 111 (11) 2122-2130
- 46 Xiang R, Liao D, Cheng T. et al. Downregulation of transcription factor SOX2 in cancer stem cells suppresses growth and metastasis of lung cancer. Br J Cancer 2011; 104 (09) 1410-1417
- 47 Bass AJ, Watanabe H, Mermel CH. et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 2009; 41 (11) 1238-1242
- 48 Justilien V, Walsh MP, Ali SA, Thompson EA, Murray NR, Fields AP. The PRKCI and SOX2 oncogenes are coamplified and cooperate to activate Hedgehog signaling in lung squamous cell carcinoma. Cancer Cell 2014; 25 (02) 139-151
- 49 Sholl LM, Barletta JA, Yeap BY, Chirieac LR, Hornick JL. Sox2 protein expression is an independent poor prognostic indicator in stage I lung adenocarcinoma. Am J Surg Pathol 2010; 34 (08) 1193-1198
- 50 Iijima Y, Seike M, Noro R. et al. Prognostic significance of PIK3CA and SOX2 in Asian patients with lung squamous cell carcinoma. Int J Oncol 2015; 46 (02) 505-512
- 51 Best SA, De Souza DP, Kersbergen A. et al. Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small-cell lung cancer with an altered immune microenvironment. Cell Metab 2018; 27 (04) 935-943.e4
- 52 Cimprich KA, Cortez D. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 2008; 9 (08) 616-627
- 53 Cao Y, Bryan TM, Reddel RR. Increased copy number of the TERT and TERC telomerase subunit genes in cancer cells. Cancer Sci 2008; 99 (06) 1092-1099
- 54 Storti CB, de Oliveira RA, de Carvalho M. et al. Telomere-associated genes and telomeric lncRNAs are biomarker candidates in lung squamous cell carcinoma (LUSC). Exp Mol Pathol 2020; 112: 104354
- 55 Wu S, Ge Y, Lin K. et al. Telomerase RNA TERC and the PI3K-AKT pathway form a positive feedback loop to regulate cell proliferation independent of telomerase activity. Nucleic Acids Res 2022; 50 (07) 3764-3776
- 56 Bieging-Rolett KT, Kaiser AM, Morgens DW. et al. Zmat3 is a key splicing regulator in the p53 tumor suppression program. Mol Cell 2020; 80 (03) 452-469.e9
- 57 Müller T, Hengstermann A. Nrf2: friend and foe in preventing cigarette smoking-dependent lung disease. Chem Res Toxicol 2012; 25 (09) 1805-1824