Molecular-genetic characteristics of rare melanocytic tumors in children

Aim of the study– to analyze the molecular genetic profile of rare melanocytic tumors in children, including skin melanoma.

Materials and methods.The study of melanocytic neoplasms tissue samples of 11 pediatric patients with melanocytic tumors was carried out by the method of targeted genomic DNA sequencing. The coding regions of genes involved in the processes of melanogenesis, melanomogenesis, proliferation, cell adhesion were investigated.

Results.It was found that in two cases in giant congenital melanocytic nevi there were mutations in the NRASgene, the same mutations were found in samples of melanomas that developed against the background of these nevi. In both cases, the developed melanomas were highly malignant. In one patient, a mutation in the CTNNB1 gene was detected in a melanoma sample, which is absent in the nevi tissue cells. In two cases of Spitz nevus, in the lentignous melanocytic nevus and in the Reed nevus, mutations in the promoter region of the TERTgene (c.-269G> A and c.-348G> C) were detected. The V600E mutation in the BRAFgene was found in dysplastic nevus and Reed nevus; in the latter case, its combination with mutations in the TERT gene promoter was revealed.In a sample of a blue nevus, the p.Q209L mutation in the GNAQ gene was detected, which is a pathognomonic genetic aberration, associated with this type of melanocytic nevus.

Conclusion.The study of the spectrum of mutations in samples of children with rare melanocytic tumors, including melanoma, indicates that the type of mutation identified was largely associated with the clinical characteristics of the nevus.

1. Noone A.M., Howlader N., Krapcho M. et al. SEER Cancer Statistics Review, 1975−2015. National Cancer Institute: Bethesda, MD, USA, 2018.

2. Шливко И.Л., Незнахина М.С., Гаранина О.Е. и др. Невусы у детей: Что определяет нашу тактику. Клиническая дерматология и венерология. 2020;19(5):669−77. [Shlivko I.L., Neznakhina M.S., Garanina O.E. et al. Nevi in children: What determines our tactics. Klinicheskaya dermatologiya i venerologiya = Clinical Dermatology and Venereology 2020;19(5):669−77. (In Russ.)].

3. Fisher J., Moustafa D., Su K.A. et al. A pediatric approach to management of skin growths in basal cell nevus syndrome. Pediatr Dermatol 2020;37(3):527−30. DOI: 10.1111/pde.14122.

4. Merkel E.A., Mohan L.S., Shi K. et al. Paediatric melanoma: clinical update, genetic basis, and advances in diagnosis. Lancet Child Adolesc Health 2019;3(9):646−54. DOI: 10.1016/S2352-4642(19)30116-6.

5. Kinsler V.A., O'Hare P., Bulstrode N. et al. Melanoma in congenital melanocytic naevi. Br J Dermatol 2017;176(5):1131−43. DOI: 10.1111/bjd.15301.

6. Polubothu S., McGuire N., Al-Olabi L. et al. Does the gene matter? Genotype-phenotype and genotype-outcome associations in congenital melanocytic naevi. Br J Dermatol 2020;182(2):434−43. DOI: 10.1111/bjd.18106.

7. Воронина В.Р. Меланоцитарные невусы у детей: Синий невус, галоневус, невус шпица и дермальные меланоцитозы. Подходы к ведению пациента с множественны-ми меланоцитарными невусами. Практика педиатра. 2019;4:28−33. [Voronina V.R. Melanocytic nevi in children: Blue nevus, halonevus, spitz nevus and dermal melanocytosis. Approaches to managing a patient with multiple melanocytic nevi. Praktika pediatra = Pediatrician Practice 2019;4:28−33. (In Russ.)].

8. Lallas A., Apalla Z., Ioannides D. et al. International Dermoscopy Society. Update on dermoscopy of Spitz/Reed naevi and management guidelines by the International Dermoscopy Society. Br J Dermatol 2017;177(3):645−55. DOI: 10.1111/bjd.15339.

9. Белышева Т.С., Любченко Л.Н., Вишневская Я.В. и др. Врожденная меланома кожи: молекулярно-генетические аспекты и особенности течения. Саркомы костей, мягких тканей и опухоли кожи. 2018;2:5−13. [Belysheva T.S., Lyubchenko L.N., Vishnevskaya Ya.V. et al. Congenital skin melanoma: Molecular genetic aspects and features of the course. Sarkomy kostej, myagkih tkanej i opuholi kozhi = Sarcomas of bones, soft tissues and skin tumors. 2018;2:5−13. (In Russ.)].

10. Olbryt M., Pigłowski W., Rajczykowski M. et al. Genetic Profiling of Advanced Melanoma: Candidate Mutations for Predicting Sensitivity and Resistance to Targeted Therapy. Target Oncol 2020;15(1):101−13. DOI: 10.1007/s11523-020-00695-0.

11. Wiesner T., He J., Yelensky R. et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun 2014;5:3116. DOI: 10.1038/ncomms4116.

12. Gray-Schopfer V.C., Cheong S.C., Chong H. et al. Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Br J Cancer 2006;95(4):496−505. DOI: 10.1038/sj.bjc.6603283.

13. Hodis E., Watson I.R., Kryukov G.V. et al. A landscape of driver mutations in melanoma. Cell 2012;150:251−63. DOI: 10.1016/j.cell.2012.06.024.

14. Shain A.H., Yeh I., Kovalyshyn I. et al. The Genetic Evolution of Melanoma from Precursor Lesions. N Engl J Med 2015;373(20):1926−36. DOI: 10.1056/NEJMoa1502583.

15. Tschandl P., Berghoff A.S., Preusser M. et al. NRAS and BRAF mutations in melanomaassociated nevi and uninvolved nevi. PLoS One 2013;8(7):e69639. DOI: 10.1371/journal.pone.0069639.

16. Zou Y., Sun Y., Zeng X. et al. Novel genetic alteration in congenital melanocytic nevus: MAP2K1 germline mutation with BRAF somatic mutation. Hereditas 2020;157(1):35. DOI: 10.1186/s41065-020-00147-9.

17. Moustafa D., Blundell A.R., Hawryluk E.B. Congenital melanocytic nevi. Curr Opin Pediatr 2020;32(4):491−97. DOI: 10.1097/MOP.0000000000000924.

18. Roh M.R., Eliades P., Gupta S., Tsao H. Genetics of melanocytic nevi. Pigment Cell Melanoma Res 2015;28(6):661−72. DOI: 10.1111/pcmr.12412.

19. Zarabi S.K., Azzato E.M., Tu Z.J. et al. Targeted next generation sequencing (NGS) to classify melanocytic neoplasms. J Cutan Pathol 2020;47(8):691−704. DOI: 10.1111/cup.13695.

20. Isales M.C., Khan A.U., Zhang B. et al. Molecular analysis of atypical deep penetrating nevus progressing to melanoma. J Cutan Pathol 2020;47(12):1150−4. DOI: 10.1111/cup.13775.

21. Lee S., Barnhill R.L., Dummer R. et al. TERT Promoter Mutations Are Predictive of Aggressive Clinical Behavior in Patients with Spitzoid Melanocytic Neoplasms. Sci Rep 2015;5:11200. DOI: 10.1038/srep11200.

22. Colebatch A.J., Ferguson P., Newell F. et al. Molecular Genomic Profiling of Melanocytic Nevi. J Invest Dermatol 2019;139(8):1762−8. DOI: 10.1016/j.jid.2018.12.033.

23. Lozada J.R., Geyer F.C., Selenica P. et al. Massively parallel sequencing analysis of benign melanocytic naevi. Histopathology 2019;75(1):29−38. DOI: 10.1111/his.13843.

24. Lu C., Zhang J., Nagahawatte P. et al. The genomic landscape of childhood and adolescent melanoma. J Invest Dermatol 2015;135(3):816−23. DOI: 10.1038/jid.2014.425.

25. Requena C., Heidenreich B., Kumar R., Nagore E. TERT promoter mutations are not always associated with poor prognosis in atypical Spitzoid tumors. Pigment Cell Melanoma Res 2017;30(2):265−8. DOI: 10.1111/pcmr.12565.

26. Волгарева Г.М., Завалишина Л.Э., Казубская Т.П. и др. Молекулярные подходы в диагностике пигментных новообразований кожи у детей: описание четырех случаев. Онкопедиатрия. 2017;4(4):294−300. [Volgareva G.M., Zavalishina L.E., Kazubskaya T.P. et al. Molecular approaches in the diagnosis of pigmented skin neoplasms in children: description of four cases. Onkopediatriya = Oncopediatrics 2017;4(4):294−300. (In Russ.)].