Levent YOLERİ, Peyker TEMİZ, Aylin TÜREL ERMERTCAN, Murat YAMAN, Mustafa Kürşat EVRENOS, Fethi Sırrı ÇAM

Clinicopathological characteristics and mutation profile of BRAF and NRAS mutation in cutaneous melanomas in the Western Turkish population

Background/aim: Malignant melanoma is the most common cause of death due to skin cancers. The most common mutations in RAFRAS pathway from tumor oncogenes are BRAF and NRAS. In this study, we analyzed the frequency of BRAF and NRAS gene mutationsand investigated their association with clinicopathological features of melanomas in the Turkish population.Materials and methods: 65 primary cutaneous melanoma were included in the study. The mutations were evaluated with real-time PCRbased PCR-array through allele-specific amplification, and the results were correlated with various clinicopathological characteristics.Results: 52.3% of the patients were female and 47.7% were male. The mean age of the patients with a mutation was lower than thosewithout mutation. 16 patients had BRAF mutation. 12 patients had NRAS mutation. NRAS mutation was statistically more common inmen (P = 0.036). The number of mitoses increased with the increase of the tumor thickness (P = 0.003). There was more mitosis in thepresence of ulceration (P = 0.05). A total of 41.7% of NRAS mutations had adjuvant chemotherapy.Conclusion: We found lower mutation rate when compared to regional studies. NRAS mutation was common in men. This is the firststudy from our region evaluating the prognostic value of clinical stage and necessity of adjuvant treatment with the presence of BRAFand NRAS mutations.

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Timar J, Vizkeleti L, Doma V, Barbai T, Raso E. Genetic progression of malignant melanoma. Cancer Metastasis Rev 2016; 35: 93-107.
Yilmaz I, Gamsizkan M, Kucukodaci Z, Berber U, Demirel D, Haholu A, Narli, G. BRAF, KIT, NRAS, GNAQ and GNA11 mutation analysis in cutaneous melanomas in Turkish population. Indian J Pathol Microbiol 2015; 58: 279-284.
Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE. et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353: 2135-2147.
Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24: 4340-4346.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W. et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949-954.
Goydos JS, Mann B, Kim HJ, Gabriel EM, Alsina J, Germino FJ, Shih W, Gorski DH. et al. Detection of B-RAF and N-RAS mutations in human melanoma. J Am Coll Surg 2005; 200: 362-370.
Scolyer RA, Long GV, Thompson JF. Evolving concepts in melanoma classification and their relevance to multidisciplinary melanoma patient care. Mol Oncol 2011; 5: 124-36.
Balch CM, Soong, S-J., Thompson, J. F. The natural history of melanoma and factors predicting outcome. In: J. F. DLM, & B. B. R. Kroon, editor. Textbook of melanoma. London: Taylor & Francis Group; 2004. pp. 181-199.
Whiteman DC, Pavan WJ, Bastian BC. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin. Pigment Cell Melanoma Res 2011; 24: 879-97.
Lovly CM, Dahlman KB, Fohn LE, Su Z, Dias-Santagata D, Hicks DJ, Hucks D, Berry E, Terry C, Duke M. et al. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PLoS One 2012; 7: e35309.
Barbour AP, Tang YH, Armour N, Dutton-Regester K, Krause L, Loffler KA, Lambie D, Burmeister B, Thomas J, Smithers BM. et al. BRAF mutation status is an independent prognostic factor for resected stage IIIB and IIIC melanoma: implications for melanoma staging and adjuvant therapy. Eur J Cancer 2014; 50: 2668-2676.
Yaman B, Akalin T, Kandiloglu G. Clinicopathological characteristics and mutation profiling in primary cutaneous melanoma. Am J Dermatopathol 2015; 37: 389-397.
Edlundh-Rose E, Egyhazi S, Omholt K, Mansson-Brahme E, Platz A, Hansson J, Lundeberg J. NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res 2006; 16: 471-478.
Viros A, Fridlyand J, Bauer J, Lasithiotakis K, Garbe C, Pinkel D, Bastian BC. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med 2008; 5: e120.
Akslen LA, Puntervoll H, Bachmann IM, Straume O, Vuhahula E, Kumar R, Molven A. Mutation analysis of the EGFR-NRASBRAF pathway in melanomas from black Africans and other subgroups of cutaneous melanoma. Melanoma Res 2008; 18: 29-35.
Venesio T, Chiorino G, Balsamo A, Zaccagna A, Petti C, Scatolini M, Pisacane A, Sarotto I, Picciotto F, Risio M. In melanocytic lesions the fraction of BRAF V600E alleles is associated with sun exposure but unrelated to ERK phosphorylation. Mod Pathol 2008; 21: 716-726.
Liu W, Kelly JW, Trivett M, Murray WK, Dowling JP, Wolfe R, Mason G, Magee J, Angel C, Dobrovic A, et al. Distinct clinical and pathological features are associated with the BRAF(T1799A(V600E)) mutation in primary melanoma. J Invest Dermatol 2007; 127: 900-905.
Saldanha G, Potter L, Daforno P, Pringle JH. Cutaneous melanoma subtypes show different BRAF and NRAS mutation frequencies. Clin Cancer Res 2006; 12: 4499-4505.
Lang J, MacKie RM. Prevalence of exon 15 BRAF mutations in primary melanoma of the superficial spreading, nodular, acral, and lentigo maligna subtypes. J Invest Dermatol 2005; 125: 575-579.
Platz A, Egyhazi S, Ringborg U, Hansson J. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol 2008; 1: 395-405.
Bauer J, Buttner P, Murali R, Okamoto I, Kolaitis NA, Landi MT, Scolyer RA, Bastian BC. BRAF mutations in cutaneous melanoma are independently associated with age, anatomic site of the primary tumor, and the degree of solar elastosis at the primary tumor site. Pigment Cell Melanoma Res 2011; 24: 345-51.
Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, Ono T, Albertson DG, Pinkel D, Bastian BC. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 2003; 95: 1878-1890.
Ellerhorst JA, Greene VR, Ekmekcioglu S, Warneke CL, Johnson MM, Cooke CP, Wang LE, Prieto, VG, Gershenwald, JE, Wei Q, et al. Clinical correlates of NRAS and BRAF mutations in primary human melanoma. Clin Cancer Res 2011; 17: 229-235.
Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol 2011; 164: 776-784.
Wu S, Kuo H, Li WQ, Canales AL, Han J, Qureshi AA. Association between BRAFV600E and NRASQ61R mutations and clinicopathologic characteristics, risk factors and clinical outcome of primary invasive cutaneous melanoma. Cancer Causes Control 2014; 25: 1379-1386.
Thomas NE, Edmiston SN, Alexander A, Groben PA, Parrish E, Kricker A, Armstrong BK, Anton-Culver H, Gruber SB, From L, et al. Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma. JAMA Oncol 2015; 1: 359- 368.
Elder DE, Gimotty PA, Guerry D. Cutaneous melanoma: estimating survival and recurrence risk based on histopathologic features. Dermatol Ther 2005; 18: 369-385.
Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011; 29: 1239- 1246.
Shim JH, Shin HT, Park J, Park JH, Lee JH, Yang JM, Kim DH, Jang KT, Lee DY. Mutational profiling of acral melanomas in Korean populations. Exp Dermatol 2017; 26: 883-888.
Jakob JA, Bassett RL, Jr., Ng CS, Curry JL, Joseph RW, Alvarado GC, Rohlfs M L, Richard J, Gershenwald JE, Kim KB, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 2012; 118: 4014-4123.
Pracht M, Mogha A, Lespagnol A, Fautrel A, Mouchet N, Le Gall F, Paumier V, Lefeuvre-Plesse C, Rioux-Leclerc N, Mosser J, et al. Prognostic and predictive values of oncogenic BRAF, NRAS, c-KIT and MITF in cutaneous and mucous melanoma. J Eur Acad Dermatol Venereol 2015; 29: 1530-1538.
Mar VJ, Liu W, Devitt B, Wong SQ, Dobrovic A, McArthur GA, Wolfe R, Kelly JW. The role of BRAF mutations in primary melanoma growth rate and survival. Br J Dermatol 2015; 173: 76-82.
Hong JW, Lee S, Kim DC, Kim KH, Song KH. Prognostic and Clinicopathologic Associations of BRAF Mutation in Primary Acral Lentiginous Melanoma in Korean Patients: A Preliminary Study. Ann Dermatol 2014; 26: 195-202.
AJCC Cancer Staging Atlas: A Companion to the Seventh Editions of the AJCC Cancer Staging Manual and Handbook. New York: Springer-Verlag; 2012. XI, 637 p.
Oltulu P, Ince B, Turk N, Uyar M, Kilinc F. High risk factors and sentinel lymph node biopsy in cutaneous squamous cell carcinoma: Analysis of prevalence and recurrence. Selcuk Med J 2018; 34: 112-118.