Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients and Tumor Tissue
2.2. Sequencing
2.3. Tumor Mutational Burden
2.4. Gene Set Enrichment Analysis
2.5. Statistics
3. Results
3.1. Driver Alterations and Signaling Cascade
3.2. Differences between Melanoma Subtypes
3.3. Characteristics of Patients Treated with Immune Checkpoint Inhibitors
3.4. Resistance Predictor for Immune Checkpoint Inhibitor Therapy
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Data availability
References
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Patient Characteristics | |
---|---|
Age at the first diagnosis of melanoma | years |
Median | 57 (46–67) |
Range | 17–85 |
Sex | no of patients (%) |
Female | 37(45) |
Male | 45 (55) |
Melanoma type | no. of patients (%) |
Cutaneous | 42 (51) |
Acral | 14 (17) |
Uveal | 8 (10) |
Mucosal | 9 (11) |
Occult | 9 (11) |
Tumor thickness of primary melanoma | mm |
Median (IQR) | 3.3 (1.8–5.1) |
Range | 0.38–5.1 |
The tumor stage at the time of tumor sequencing | no. of patients (%) |
Stage II | 5 (6) |
Stage IV | 77 (94) |
Immunotherapy | 76/82 (93) |
Targeted therapy | 21 (26) |
Chemotherapy | 4 (5) |
No systemic treatment | 5 (6) |
Origin of the tissue sequenced | no of patients (%) |
Lymph node | 19 (23) |
Other metastasis | 57 (70) |
Primary melanoma | 6 (7) |
Pretreatment of tissue sequenced | no. of patients (%) |
Tissue therapy naïve | 52 (63) |
Tissue progressive under ICI | 18 (22) |
Tissue progressive under targeted therapy | 8 (10) |
Tissue progressive under chemotherapy | 4 (5) |
Genetic Characteristics of the 82 Patients | Cutaneous | Acral | Mucosal | Uveal | Occult |
---|---|---|---|---|---|
(n = 42) | (n = 14) | (n = 9) | (n = 8) | (n = 9) | |
Tumor mutation burden (TMB) | |||||
Median (IQR) | 9.4 (6–14.6) | 1.5 (1–5.3) | 3.2 (2–3.8) | 2.8 (1.6–4) | 7.5 (4.8–23.5) |
Range | 0–36.444 | 0.51–151.8 | 1.1–6.a | 1.5–4.2 | 0–40.6 |
Comparison to cutaneous subtype 1 | p = 0.0027 * | p = 0.0003 * | p = 0.0003 * | p = 0.837 | |
Single nucleotide variants (SNVs) | |||||
Median (IQR) | 10 (6–15) | 3 (1–7.3) | 3 (2–4.5) | 3.5 (2–4) | 11 (4–25) |
Range | 0–33 | 0–156 | 1–6 | 2–4 | 1–44 |
Comparison to cutaneous subtype 1 | p = 0.0134 | p = 0.0005 * | p = 0.0008 * | p = 0.995 | |
Copy number variants (CNVs) | |||||
Median (IQR) | 8 (3.5–19) | 12.5 (5.8–25) | 33 (17.5–39) | 8 (4.5–11) | 16 (0.5–23) |
Range | 0–44 | 0–48 | 0–43 | 4–19 | 0–29 |
Comparison to cutaneous subtype 1 | p = 0.321 | p = 0.002 | p = 0.995 | p = 0.587 |
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Hilke, F.J.; Sinnberg, T.; Gschwind, A.; Niessner, H.; Demidov, G.; Amaral, T.; Ossowski, S.; Bonzheim, I.; Röcken, M.; Riess, O.; et al. Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients. Cancers 2020, 12, 2359. https://doi.org/10.3390/cancers12092359
Hilke FJ, Sinnberg T, Gschwind A, Niessner H, Demidov G, Amaral T, Ossowski S, Bonzheim I, Röcken M, Riess O, et al. Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients. Cancers. 2020; 12(9):2359. https://doi.org/10.3390/cancers12092359
Chicago/Turabian StyleHilke, Franz J., Tobias Sinnberg, Axel Gschwind, Heike Niessner, German Demidov, Teresa Amaral, Stephan Ossowski, Irina Bonzheim, Martin Röcken, Olaf Riess, and et al. 2020. "Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients" Cancers 12, no. 9: 2359. https://doi.org/10.3390/cancers12092359