Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy
Abstract
:1. Introduction
2. Materials and Methods
2.1. Clinical Review
2.2. Sample Collection and Nucleic Acid Isolation
2.3. Next-Generation Whole-Exome Sequencing and Analysis
2.4. Next-Generation RNA Sequencing and Analysis
2.5. Data Availability
2.6. NFKBIE Wildtype and G34E Expression Vectors
2.7. NF-kB Luciferase Reporter Assay
2.8. Cell Surface Protein Analysis
3. Results
3.1. Clinical Analysis
3.2. Mutated Genes Enriched in Patients that Responded to Immunotherapy Included the Hotspot Variant G34E in NFKBIE, (NFkB Inhibitor Epsilon) the Gene that Encodes for I-kappa-B-Epsilon (IkBe), a Negative Regulator of NFkB
3.3. Enrichment of Mutations in NFKBIE-Related Genes Found in Responders Suggests Aberrations in the NFkB Signaling Pathway
3.4. Mutations in NFKBIE-Related Genes Correlate with Clinical Metrics Used to Measure Patient Responses to Immunotherapy
3.5. Gene Set Enrichment Analysis (GSEA) Suggests that Genes Involved in NFkB Signaling Are Differentially Expressed, Including Upregulation of CD83 in Our Responder Cohort
3.6. G34E of NFKBIE Is Likely a Loss-of-Function Variant, Resulting in Activation of NFkB Pathway
4. Discussion
5. Conculusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Total Cohort | 52 |
---|---|
Sex | |
Male | 34 (65%) |
Female | 18 (35%) |
Age (year) | |
Median | 56 |
Range | 22–87 |
Mutational Analysis | |
BRAF (V600E/K) | 11 (21%) |
NRAS (G13_/Q61_) | 4 (7%) |
NF1 | 11 (21%) |
Immune Checkpoint Therapy | |
Nivolomab | 11 (21%) |
Pembrolizumab | 41 (79%) |
Response | |
Complete Response | 6 (11%) |
Partial Response | 15 (28%) |
Stable Disease | 16 (30%) |
Progressive Disease | 15 (28%) |
Melanoma Subtype | |
Superficial Spreading | 17 (33%) |
Nodular | 13 (25%) |
Desmoplastic | 4 (7%) |
Unknown Primary | 5 (9%) |
Acral | 3 (5%) |
Mucosal | 4 (7%) |
Ocular | 1 (2%) |
Other | 5 (9%) |
Stage at Diagnosis | |
III Unresectable | 1 (2%) |
IIIB | 2 (3%) |
IIIC | 10 (19%) |
IV | 39 (75%) |
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Amato, C.M.; Hintzsche, J.D.; Wells, K.; Applegate, A.; Gorden, N.T.; Vorwald, V.M.; Tobin, R.P.; Nassar, K.; Shellman, Y.G.; Kim, J.; et al. Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy. Cancers 2020, 12, 1943. https://doi.org/10.3390/cancers12071943
Amato CM, Hintzsche JD, Wells K, Applegate A, Gorden NT, Vorwald VM, Tobin RP, Nassar K, Shellman YG, Kim J, et al. Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy. Cancers. 2020; 12(7):1943. https://doi.org/10.3390/cancers12071943
Chicago/Turabian StyleAmato, Carol M., Jennifer D. Hintzsche, Keith Wells, Allison Applegate, Nicholas T. Gorden, Victoria M. Vorwald, Richard P. Tobin, Kelsey Nassar, Yiqun G. Shellman, Jihye Kim, and et al. 2020. "Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy" Cancers 12, no. 7: 1943. https://doi.org/10.3390/cancers12071943