Skin Photodamage and Melanomagenesis: A Comprehensive Review
Simple Summary
Abstract
1. Introduction
2. Epidemiology
3. UVR-Induced DNA Damage
3.1. UVB Radiation in Melanoma Development
3.2. UVA Radiation in Melanoma Development
4. Infrared Radiation (IRA)/UVR Cross-Talk in Melanoma Development
5. Genetic Predisposition
6. Cellular Response to UV-Induced DNA Damage
6.1. Nucleotide Excision Repair (NER)
6.2. Base Excision Repair (BER)
6.3. Translesion Synthesis (TLS)
7. UVR-Mediated Inflammation and Immunosuppression in Skin Carcinogenesis
8. Pathogenesis of Melanoma: Diagnostic and Surgical Controversies
8.1. Diagnostic Aspects
8.2. Molecular and Histopathologic Characteristics and Their Implications in Clinical Practice
8.2.1. Molecular Biomarkers in Clinical Practice
8.2.2. Immunohistochemical Biomarkers
8.2.3. Etiopathogenic and Molecular Divergence by Sun Exposure Pattern
8.3. Surgical Management
8.4. Controversies
8.5. Future Directions and Clinical Perspectives
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
6-4PPs | 6-4 photoproducts |
8-oxodGuo | 7,8-dihydro-8-oxyguanine |
AI | Artificial Intelligence |
BER | Base Excision Repair |
CDPs | Cyclobutane Pyrimidine Dimers |
CM | Cutaneous Melanoma |
CSD | Chronically Sun-Damaged |
ctDNA | Circulating Tumor DNA |
iNOS | Inducible Nitric Oxide Synthase |
IR | Infrared Radiation |
LM | Lentigo Maligna |
LMM | Lentigo Maligna Melanoma |
NO | Nitric Oxide |
NOX | NADPH Oxidase |
NER | Nucleotide Excision Repair |
O2− | Superoxide Radical Ions |
O3 | Ozone |
ONOO− | Peroxynitrite |
RCM | Reflectance Confocal Microscopy |
ROS | Reactive Oxygen Species |
TLS | Translesion Synthesis |
TMB | Tumoral Mutation Burden |
UVR | Ultraviolet Radiation |
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Category | Gene/Pathway | Mutation Type | Effect | Melanoma Risk | Reference |
---|---|---|---|---|---|
Pigmentation | MC1R | Variants (especially red hair color—RHC-associated) | Alters pigmentation, UV sensitivity, DNA repair | Increased (doubles risk with CDKN2A mutations) | [33,50,51] |
ASIP | Variants | Alters melanocortin signaling | Slightly increased | [50] | |
TYR | Variants | Alters melanin synthesis | Slightly increased | [50] | |
Tumor Suppressor | CDKN2A (p16/INK4a, p14/ARF) | Germline mutations, Loss of function | Deregulates cell cycle, impairs senescence, affects oxidative stress | High (67% lifetime risk with heterozygous loss) | [52,53,54,55,56,57,58,59,60,61,62,63,64] |
RB | Germline mutations | Reduces tumor suppressor activity | Increased | [65,66] | |
PTEN | Inactivating mutations, deletions, epigenetic silencing | Activates AKT signaling | Increased | [67,68] | |
NF1 | Loss-of-function mutations | Hyperactivates NRAS, MAPK, and PI3K/AKT pathways | Increased (especially with sun damage) | [69,70] | |
Signaling Pathway (MAPK) | BRAF | V600E (most common), V600R, V600D | Constitutive activation of kinase activity, activates MEK/ERK | Highly increased | [71,72,73,74,75,76] |
NRAS | Q61R, Q61K (most common) | Activates MAPK pathway | Increased | [77,78] | |
RAS (KRAS, HRAS, NRAS) | Mutations | Activates RAF kinases | Increased | [76] | |
Signaling Pathway (WNT) | CTNNB1 | Mutations | Stabilizes β-catenin, activates transcription | Increased (2–23% of cases) | [79,80] |
Receptor Tyrosine Kinase (RTK) | EGFR | Gene copy number gains, point mutations | Dysregulation | Increased | [81] |
HGF/MET | Gene copy number gains, point mutations | Dysregulation | Increased | [82] | |
KIT | L576P mutation | Activates KIT signaling | Increased (small number of melanomas) | [83] | |
PTPRD | Deletions | Loss of phosphatase activity | Increased | [84] | |
PDGFR, IGFR | Upregulation | Increased signaling | Increased | [85] | |
Transcription Factor | MITF | Amplification, E318K mutation | Drives melanocytic lineage, survival, growth, differentiation | Increased | [86,87,88,89] |
MYC | Overexpression | Enhances melanoma progression | Increased | [90] | |
TBX2 | Amplification | Represses p14ARF and p21CIP1 | Increased | [91,92] | |
TERT | Promoter mutations (C→T) | Creates ETS transcription factor binding sites | Increased proliferation | [93,94] | |
Epigenetic Factors | Multiple genes | Differential methylation (UV exposure signature) | May drive melanoma development | Increased | [95,96] |
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Manganelli, M.; Stabile, G.; Scharf, C.; Podo Brunetti, A.; Paolino, G.; Giuffrida, R.; Bigotto, G.D.; Damiano, G.; Mercuri, S.R.; Sallustio, F.; et al. Skin Photodamage and Melanomagenesis: A Comprehensive Review. Cancers 2025, 17, 1784. https://doi.org/10.3390/cancers17111784
Manganelli M, Stabile G, Scharf C, Podo Brunetti A, Paolino G, Giuffrida R, Bigotto GD, Damiano G, Mercuri SR, Sallustio F, et al. Skin Photodamage and Melanomagenesis: A Comprehensive Review. Cancers. 2025; 17(11):1784. https://doi.org/10.3390/cancers17111784
Chicago/Turabian StyleManganelli, Michele, Giorgio Stabile, Camila Scharf, Antonio Podo Brunetti, Giovanni Paolino, Roberta Giuffrida, Gianmarco Diego Bigotto, Giuseppe Damiano, Santo Raffaele Mercuri, Fabio Sallustio, and et al. 2025. "Skin Photodamage and Melanomagenesis: A Comprehensive Review" Cancers 17, no. 11: 1784. https://doi.org/10.3390/cancers17111784
APA StyleManganelli, M., Stabile, G., Scharf, C., Podo Brunetti, A., Paolino, G., Giuffrida, R., Bigotto, G. D., Damiano, G., Mercuri, S. R., Sallustio, F., Mangano, E., Bordoni, R., De Nardi, P., Guida, G., Foti, C., Argenziano, G., Longo, C., Pellacani, G., Rizzo, N., ... Rongioletti, F. (2025). Skin Photodamage and Melanomagenesis: A Comprehensive Review. Cancers, 17(11), 1784. https://doi.org/10.3390/cancers17111784