GENETIC ALTERATIONS IN MELANOMA
Abstract
Melanoma, an aggressive skin tumor with a high mortality rate in advanced stages, represents a global health challenge. Genetic alterations play a pivotal role in its onset and progression.
Recent studies have established a connection between melanoma and changes in signaling pathways involved in cell cycle regulation, notably the MAPK pathway. Over 80% of melanomas exhibit mutations in BRAF, RAS, and NF1, key genes of this signaling chain. Targeted therapies such as BRAF and MEK inhibitors have been developed. However, frequent secondary resistance to this therapy, as well as the existence of melanoma without these mutations, known as "triple wild type", emphasizes the need for further genetic research and improvement of therapeutic strategies.
Mutations in genes like KIT, GNAQ/11, PTEN, and TERT are also associated with melanoma pathogenesis, and some of them with specific subtypes of this tumor. Hereditary predisposition is detected in only 5-10% of cases, with CDKN2A and CDK4 identified as the two most common genes in the familial form of melanoma.
Exposure to UV radiation has been found as the primary risk factor in shaping the genetic profile of melanoma, leading to the development of "UV signature mutations" that cause further errors in DNA replication and melanomagenesis. Additionally, variations in genes regulating the synthesis of the protective pigment eumelanin during sun exposure, such as MC1R and MITF, pose risks for this disease.
Studying precursor lesions, such as melanocytic nevi, has contributed to the understanding of melanoma's genetic evolution. Identification of mutations like BRAF V600E in these lesions highlights the role of additional genetic changes in malignant transformation.
Future research is expected to identify new genetic markers that would improve understanding, prevention, and diagnosis of melanoma, which will enable a personalized approach to treatment with improved efficiency and reduced side effects of therapy.
References
2. Clinical Practice Guidelines for Menagment of Melanoma in Australia and New Zeland 2018. Available from : https://wiki.cancer.org.au/australia/Guidelines:Melanoma [
3. Strashilov S, Yordanov A. Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances. International journal of molecular sciences. 2021;22(12).
4. Pons M, Quintanilla M. Molecular biology of malignant melanoma and other cutaneous tumors. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2006;8(7):466-74.
5. Abdo JF, Sharma A, Sharma R. Role of Heredity in Melanoma Susceptibility: A Primer for the Practicing Surgeon. The Surgical clinics of North America. 2020;100(1):13-28.
6. Patel H, Yacoub N, Mishra R, White A, Long Y, Alanazi S, et al. Current Advances in the Treatment of BRAF-Mutant Melanoma. Cancers. 2020;12(2).
7. Miller AJ, Mihm MC, Jr. Melanoma. The New England journal of medicine. 2006;355(1):51-65.
8. Acosta AM, Kadkol SS. Mitogen-Activated Protein Kinase Signaling Pathway in Cutaneous Melanoma: An Updated Review. Archives of pathology & laboratory medicine. 2016;140(11):1290-6.
9. Cancer Genome Atlas N. Genomic Classification of Cutaneous Melanoma. Cell. 2015;161(7):1681-96.
10. Castellani G, Buccarelli M, Arasi MB, Rossi S, Pisanu ME, Bellenghi M, et al. BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers. Cancers. 2023;15(16).
11. Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2018;31(1):24-38.
12. Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, et al. The role of BRAF V600 mutation in melanoma. Journal of translational medicine. 2012;10:85.
13. Zhang T, Dutton-Regester K, Brown KM, Hayward NK. The genomic landscape of cutaneous melanoma. Pigment cell & melanoma research. 2016;29(3):266-83.
14. Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nature genetics. 2015;47(9):996-1002.
15. Palmieri G, Colombino M, Casula M, Manca A, Mandala M, Cossu A, et al. Molecular Pathways in Melanomagenesis: What We Learned from Next-Generation Sequencing Approaches. Current oncology reports. 2018;20(11):86.
16. Pipek O, Vizkeleti L, Doma V, Alpar D, Bodor C, Karpati S, et al. The Driverless Triple-Wild-Type (BRAF, RAS, KIT) Cutaneous Melanoma: Whole Genome Sequencing Discoveries. Cancers. 2023;15(6).
17. Pham DDM, Guhan S, Tsao H. KIT and Melanoma: Biological Insights and Clinical Implications. Yonsei medical journal. 2020;61(7):562-71.
18. Gong HZ, Zheng HY, Li J. The clinical significance of KIT mutations in melanoma: a meta-analysis. Melanoma research. 2018;28(4):259-70.
19. Teixido C, Castillo P, Martinez-Vila C, Arance A, Alos L. Molecular Markers and Targets in Melanoma. Cells. 2021;10(9).
20. Zuo Q, Liu J, Huang L, Qin Y, Hawley T, Seo C, et al. AXL/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma. Oncogene. 2018;37(24):3275-89.
21. Bai X, Kong Y, Chi Z, Sheng X, Cui C, Wang X, et al. MAPK Pathway and TERT Promoter Gene Mutation Pattern and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 Cases. Clinical cancer research : an official journal of the American Association for Cancer Research. 2017;23(20):6120-7.
22. Guo Y, Chen Y, Zhang L, Ma L, Jiang K, Yao G, et al. TERT Promoter Mutations and Telomerase in Melanoma. Journal of oncology. 2022;2022:6300329.
23. Rossi M, Pellegrini C, Cardelli L, Ciciarelli V, Di Nardo L, Fargnoli MC. Familial Melanoma: Diagnostic and Management Implications. Dermatology practical & conceptual. 2019;9(1):10-6.
24. Zocchi L, Lontano A, Merli M, Dika E, Nagore E, Quaglino P, et al. Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management. Journal of clinical medicine. 2021;10(16).
25. Sample A, He YY. Mechanisms and prevention of UV-induced melanoma. Photodermatology, photoimmunology & photomedicine. 2018;34(1):13-24.
26. Khan AQ, Travers JB, Kemp MG. Roles of UVA radiation and DNA damage responses in melanoma pathogenesis. Environmental and molecular mutagenesis. 2018;59(5):438-60.
27. Swope VB, Abdel-Malek ZA. MC1R: Front and Center in the Bright Side of Dark Eumelanin and DNA Repair. International journal of molecular sciences. 2018;19(9).
28. Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. The Genetic Evolution of Melanoma from Precursor Lesions. The New England journal of medicine. 2015;373(20):1926-36.
29. Sung WW, Chang CH. Nevi, dysplastic nevi, and melanoma: Molecular and immune mechanisms involving the progression. Tzu Chi Med J. 2022;34(1):1-7.
30. Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, et al. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov. 2012;11(11):873-86.
31. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-65.
32. Najem A, Krayem M, Perdrix A, Kerger J, Awada A, Journe F, et al. New Drug Combination Strategies in Melanoma: Current Status and Future Directions. Anticancer Res. 2017;37(11):5941-53.