KEAP1/NRF2 Mutations in Stem Cells Define an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients’ Informed Consent, Tissue Collection, and Processing
2.2. Flow Cytometry and Cell Sorting
2.3. Genomic DNA Extraction, PCR Amplification, and Sanger Sequencing
2.4. Cell Lines, Cell Cultures, and Cell Viability Assay
2.5. Sphere Formation Assay
2.6. TCGA and HNC-MSKCC Public Data Sets
2.7. Statistical Analysis
3. Results
3.1. Keap1/Nrf2 Mutation Analysis in HN-CSCs
3.2. Keap1/Nrf2 Mutations in HN-CSCs Are Associated with Inferior Survival Outcomes
3.3. Keap1/Nrf2 Mutant Cells Experience Therapeutic Resistance and Chemosensitivity to Glutamine Inhibitor
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | N (%) | |
---|---|---|
Age at diagnosis | Median (IQ range) | 59.6 (48.3–72.1) |
Sex | Male | 41 (82) |
Female | 9 (18) | |
HPV status | Positive | 7 (14) |
Negative | 43 (86) | |
Histology | Oral cavity | 15 (30) |
Base of tongue | 9 (18) | |
Oropharyngeal | 18 (36) | |
Laryngeal | 8 (16) | |
Primary treatment | ||
Surgery > XRT with or without chemo | 5 (10) | |
Concurrent chemo-XRT | 11 (22) | |
Induction > definitive therapy | 13 (26) | |
Surgery > XRT > Salvage chemo/XRT | 0 | |
Surgery alone | 12 (24) | |
XRT alone | 9 (18) | |
Exposure to platinum in metastatic setting | ||
No | 12 (24) | |
Yes | 38 (76) | |
Exposure to cetuximab in a metastatic setting | ||
No | 31 (62) | |
Yes | 19 (38) | |
Performance status | ||
0–1 | 36 (72) | |
2 | 14 (28) |
Parameters | Tumors with HN-CSC Mutations (n = 13) | Tumors without HN-CSC Mutations (n = 37) | p-Value a |
---|---|---|---|
Age at diagnosis, y, Median | 62.5 (58.1–73.9) | 57.1 (54.7–81.3) | 0.27 b |
Tumor size (cm), Median | 3.8 (11.9–4.2) | 3.2 (1.6–4.6) | 0.10 b |
Disease progression, %, (No./total No.) | 53 (7/13) | 5 (2/37) | 0.04 |
Lung metastasis, % (No./total No.) | 69 (9/13) | 5 (2/37) | 0.001 |
Lymph nodes | 46 (6/13) | 5 (2/37) | 0.001 |
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Islam, S.S.; Karakas, B.; Aboussekhra, A.; Noman, A.S.M. KEAP1/NRF2 Mutations in Stem Cells Define an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure. Cancers 2023, 15, 5006. https://doi.org/10.3390/cancers15205006
Islam SS, Karakas B, Aboussekhra A, Noman ASM. KEAP1/NRF2 Mutations in Stem Cells Define an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure. Cancers. 2023; 15(20):5006. https://doi.org/10.3390/cancers15205006
Chicago/Turabian StyleIslam, Syed S., Bedri Karakas, Abdelilah Aboussekhra, and Abu Shadat M. Noman. 2023. "KEAP1/NRF2 Mutations in Stem Cells Define an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure" Cancers 15, no. 20: 5006. https://doi.org/10.3390/cancers15205006
APA StyleIslam, S. S., Karakas, B., Aboussekhra, A., & Noman, A. S. M. (2023). KEAP1/NRF2 Mutations in Stem Cells Define an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure. Cancers, 15(20), 5006. https://doi.org/10.3390/cancers15205006