Document Type : Original Research


1 Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

3 Maternal-Fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran


Background & Objective: Acral melanoma (AM) is a common type of cutaneous melanoma that occurs in the skin of the palms, soles, and nail beds. This malignancy, like other types of cancer, has different genetic alterations. To date, despite decades of research the roles of oncogenic BRAF mutations in the pathogenesis of AM has not been fully clarified. The present study was designed to identify V600E mutation in patients with AM from the south of Iran. 
Methods: The samples were collected from the pathology lab archive of Shiraz University of Medical Sciences (2015-2020). A total of 41 patients with primary invasive AM underwent excisional biopsy or amputation were collected to evaluate BRAF V600E mutation using Polymerase Chain Reaction (PCR) and Sanger sequencing.
Results: Total number of 41cases (21 male and 20 female) and age range of 34-87 years were enrolled. The histological subtypes were 24 acral lentiginous melanomas (ALM), 10 cases of nodular melanoma (NM), and 7 cases of superficial spreading melanoma (SSM). In our study, only one case (a 44-year-old male with nail bed AM and the histological subtype of acral lentigenous melanoma) showed BRAF-V600E mutation. 
Conclusion: These findings suggest that the population of our interest showed a very low prevalence of this mutation providing novel insights into the pathobiology of AM and its related treatment. 


Main Subjects

Copyright © 2021. This is an open-access article distributed under the terms of the Creative Commons Attribution- 4.0 International License which permits Share, copy and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, even commercially.

  1. Barra-Martínez R, Herrera-González N, Fernández-Ramírez F, Torres L. Acral Melanoma-A Distinct Molecular and Clinical Subtype. Melanoma-Current Clinical Management and Future Therapeutics. 2015. [DOI:10.5772/59093]
  2. Forman SB, Ferringer TC, Peckham SJ, Dalton SR, Sasaki GT, Libow LF, et al. Is superficial spreading melanoma still the most common form of malignant melanoma? 2008;58(6):1013-20. [DOI:10.1016/j.jaad.2007.10.650] [PMID]
  3. Ito T, Kaku-Ito Y, Murata M, Furue K, Shen CH, Oda Y, et al. Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival. J Clin Med. 2020;9(3):690. [DOI:10.3390/jcm9030690] [PMID] [PMCID]



  1. Suh MS, Choi YD, Lee JB, Lee SC, Won YH, Yun SJ. Sensitivity and Usefulness of VE1 Immunohistochemical Staining in Acral Melanomas with BRAF Mutation. Ann Dermatol. 2018;30(5):556-61. [DOI:10.5021/ad.2018.30.5.556] [PMID] [PMCID]
  2. Ito T, Kaku-Ito Y, Murata M, Ichiki T, Kuma Y, Tanaka Y, et al. Intra- and Inter-Tumor BRAF Heterogeneity in Acral Melanoma: An Immunohistochemical Analysis. Int J Mol Sci. 2019;20(24):6191. [DOI:10.3390/ijms20246191] [PMID] [PMCID]
  3. Kim JY, Choi M, Jo SJ, Min HS, Cho KH. Acral lentiginous melanoma: indolent subtype with long radial growth phase. Am J Dermatopathol. 2014;36(2):142-7. [DOI:10.1097/DAD.0b013e31829bea8b] [PMID]



  1. Daniel VT, Crawford A, Kiefe CI, Mahmoud BH. Recurrence and Mortality of Melanoma In Situ of the Trunk or Extremities: A Surveillance, Epidemiology, and End Results Analysis. Dermatologic Surgery: Official Publication for American Society for Dermatologic Surgery [et al]. 2020. [DOI:10.1097/DSS.0000000000002417] [PMID]
  2. Dimitriou F, Krattinger R, Ramelyte E, Barysch MJ, Micaletto S, Dummer R, et al. The World of Melanoma: Epidemiologic, Genetic, and Anatomic Differences of Melanoma Across the Globe. Curr Oncol Rep. 2018;20(11):87. [DOI:10.1007/s11912-018-0732-8] [PMID]
  3. Timar J, Vizkeleti L, Doma V, Barbai T, Raso E. Genetic progression of malignant melanoma. Cancer Metastasis Rev. 2016;35(1):93-107. [DOI:10.1007/s10555-016-9613-5] [PMID]
  4. Moon KR, Choi YD, Kim JM, Jin S, Shin M-H, Shim H-J, et al. Genetic alterations in primary acral melanoma and acral melanocytic nevus in Korea: common mutated genes show distinct cytomorphological features. Journal of Investigative Dermatology. 2018;138(4):933-45. [DOI:10.1016/j.jid.2017.11.017] [PMID]
  5. Dibb NJ, Dilworth SM, Mol CD. Switching on kinases: oncogenic activation of BRAF and the PDGFR family. Nat Rev Cancer. 2004;4(9):718-27. [DOI:10.1038/nrc1434] [PMID]
  6. Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62(23):6997-7000.
  7. Tetzlaff MT, Pattanaprichakul P, Wargo J, Fox PS, Patel KP, Estrella JS, et al. Utility of BRAF V600E immunohistochemistry expression pattern as a surrogate of BRAF mutation status in 154 patients with advanced melanoma. Human pathology. 2015;46(8):1101-10. [DOI:10.1016/j.humpath.2015.04.012] [PMID] [PMCID]
  8. Shinozaki M, Fujimoto A, Morton DL, Hoon DS. Incidence of BRAF oncogene mutation and clinical relevance for primary cutaneous melanomas. Clin Cancer Res. 2004;10(5):1753-7. [DOI:10.1158/1078-0432.CCR-1169-3] [PMID]
  9. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209-21. [DOI:10.1016/j.cell.2009.12.040] [PMID] [PMCID]
  10. Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. The Journal of clinical investigation. 2005;115(1):94-101. [DOI:10.1172/JCI23237] [PMID] [PMCID]
  11. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-16. [DOI:10.1056/NEJMoa1103782] [PMID] [PMCID]
  12. 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. Mod Pathol. 2018;31(1):24-38. [DOI:10.1038/modpathol.2017.104] [PMID] [PMCID]
  13. Menzies AM, Haydu LE, Visintin L, Carlino MS, Howle JR, Thompson JF, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18(12):3242-9. [DOI:10.1158/1078-0432.CCR-12-0052] [PMID]
  14. Greaves WO, Verma S, Patel KP, Davies MA, Barkoh BA, Galbincea JM, et al. Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma. J Mol Diagn. 2013;15(2):220-6. [DOI:10.1016/j.jmoldx.2012.10.002] [PMID] [PMCID]
  15. Forbes SA, Bhamra G, Bamford S, Dawson E, Kok C, Clements J, et al. The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr Protoc Hum Genet. 2008;Chapter 10(1):Unit 10 1. [DOI:10.1002/0471142905.hg1011s57] [PMID] [PMCID]
  16. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-54. [DOI:10.1038/nature00766] [PMID]
  17. Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, et al. V600EBRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. 2009;106(11):4519-24. [DOI:10.1073/pnas.0900780106] [PMID] [PMCID]
  18. Ghasemi M, Vahedi Larijani L, Emadian O, Yazdani J, Sajadianfar A, Abediankenari S. Immunohistochemical Investigation of Mutant BRAF V600E in Common Pigmented Skin Neoplasms, Study on a Sample of Iranian Patients. Iran J Pathol. 2019;14(1):8-16. [DOI:10.30699/ijp.14.1.8] [PMID] [PMCID]
  19. Huang WK, Kuo TT, Wu CE, Cheng HY, Hsieh CH, Hsieh JJ, et al. A comparison of immunohistochemical and molecular methods used for analyzing the BRAF V600E gene mutation in malignant melanoma in Taiwan. 2016;12(4):403-8. [DOI:10.1111/ajco.12574] [PMID]
  20. Saldanha G, Purnell D, Fletcher A, Potter L, Gillies A, Pringle JHJIjoc. High BRAF mutation frequency does not characterize all melanocytic tumor types. 2004;111(5):705-10. [DOI:10.1002/ijc.20325] [PMID]
  21. Dika E, Veronesi G, Altimari A, Riefolo M, Ravaioli GM, Piraccini BM, et al. BRAF, KIT, and NRAS Mutations of Acral Melanoma in White Patients. Am J Clin Pathol. 2020;153(5):664-71. [DOI:10.1093/ajcp/aqz209] [PMID]
  22. Si L, Kong Y, Xu X, Flaherty KT, Sheng X, Cui C, et al. Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort. Eur J Cancer. 2012;48(1):94-100. [DOI:10.1016/j.ejca.2011.06.056] [PMID]
  23. Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239-46. [DOI:10.1200/JCO.2010.32.4327] [PMID]
  24. Ghanadan A, Yousefi T, Kamyab-Hesari K, Azhari V, Nasimi M. Prevalence and Main Determinants of BRAF V600E Mutation in Dysplastic and Congenital Nevi. Iran J Pathol. 2021;16(1):51-6. [DOI:10.30699/ijp.2020.130968.2451] [PMID] [PMCID]