İbrahim İBİLOGLU, Ulas ALABALIK, Ayşe Nur KELEŞ, Gülay AYDOĞDU, Hüseyin BÜYÜKBAYRAM

Diyarbakır bölgesinde malign melanom hastalarının BRAF mutasyonu analizi

Amaç: Bu çalışmada Diyarbakır yöresindeki malign melanoma (MM) vakalarında BRAF V600E mutasyon oranlarını belirlemeyi, mutasyon oranlarının prognostik parametrelerle ilişkisini araştırmayı ve sonuçları Türkiye’nin batısındaki değerler ile karşılaştırılması amaçlanmıştır. Gereç ve Yöntem: Ocak 2014-Temmuz 2019 tarihleri arasında Dicle Üniversite Tıp Fakültesi Patoloji AD’da tanı alan primer MM ve metastatik MM olmak üzere 93 MM olgusu dahil edildi. Hastaların real-time polimeraz zincir reaksiyonu (PCR) yöntemi ile çalışılan BRAF V600E mutasyon sonuçları ile prognostik parametreler karşılaştırıldı. Bulgular: MM tanılı 93 hastada BRAF V600E mutasyon oranı %21,5 (n=20) olup gövde ve baş-boyun yerleşimli tümörlerde, kutanöz ve mukozal yerleşimli tümörlerde, Clark evre V tümörlerde, 0-2 mm arası çapa sahip tümörlerde, Ki-67 proliferasyonu %11-20 arasında olanlarda, ülserli olmayan tümörlerde, kronik güneş maruziyeti olanlarda daha yüksek oranda izlenmiştir. Sonuç: Diyarbakır yöresinde BRAF mutasyonunu Türkiye’nin batısındaki değerlere göre daha düşük bulduk. Bunun nedeninin bölgemizde akral lentijinöz melanom (ALM)’un daha sık izlenmesi olduğunu düşünmekteyiz. Küçük çaplı tümörlerde BRAF V600E mutasyonunun daha fazla izlenmesine karşın yüksek Clark evre tümörlerde daha fazla görülmesi, mutasyonun daha sonra tümörün ileri evrelerinde de ortaya çıkabileceğini akla getirmiştir. Yüksek olgu serileri ile yapılacak çalışmalar BRAF ve prognostik değerler arasındaki korelasyonları ortaya çıkarabilir ve tedavi için hasta seçiminde yararlı olabilir.

BRAF mutation analysis of malignant melanoma cases in Diyarbakır, Turkey

Purpose: The aim of this study was to determine BRAF V600E mutation rates of malignant melanoma (MM) cases in the Diyarbakır region in this study to investigate the relationship between mutation rate of prognostic parameters. We also aimed to compare the results with values from west Turkey. Materials and Methods: Between all cases of MM, including primary MM and metastatic MM diagnosed at Dicle University Medical Faculty Pathology Department between January 2014 and July 2019 were included. The BRAF V600E mutation results, which were studied with the real-time polyemerase chain reaction (PCR) method, were compared with the prognostic parameters. Results: In 93 patients with MM, the BRAF V600E mutation rate was 21.5% (n = 20). Trunk and head-neck tumors, cutaneous and mucosal tumors, Clark stage V tumors, tumors with a diameter of 0-2 mm, Ki-67 proliferation between 11-20%, non-ulcerous tumors, chronic sun exposure in a higher rate was detected. Conclusions: BRAF mutations in Diyarbakir region were found to be lower than the value in the region in the west of Turkey. We think that the reason for this is more frequent monitoring of acral lentiginous melanoma (ALM) in our region. Although the BRAF V600E mutation was observed more in small-sized tumors, it was seen more in high Clark stage tumors, suggesting that the mutation may occur later in the advanced stages of the tumor. Studies with high case series may reveal possible correlations between BRAF and prognostic values and may be useful in patient selection for treatment.

Keywords:

malignant melanoma, BRAF,

PDF

___

1. Kang X , Zeng Y , Liang J , et al. Aberrations and clinical signifi- cance of BRAF in malignant melanoma: a series of 60 cases in Chinese Uyghur. Medicine (Baltimore). 2018;97:9509.
2. Sharma K , Mohanti BK , Rath GK . Malignant melanoma: A ret- rospective series from a regional cancer center in India. J Can Res Ther. 2009;5:173–80.
3. Byrd-Miles K , Toombs EL , Peck GL . Skin cancer in individuals of African, Asian, Latin-American, and American-Indian descent: differences in incidence, clinical presentation, and survival com- pared to Caucasians. J Drugs Dermatol. 2007;6:10–16.
4. Goel VK , Lazar AJ , Warneke CL et al. Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol. 2006;126:154–60.
5. Sasaki Y, Niu C, Makino R et al. BR AF point mutations in primary melanoma show different prevalences by subtype. J Invest Dermatol. 2004;123:177–83.
6. Garnett M, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004;6:313–9.
7. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.
8. Robinson M, Cobb M. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997;9:180–6.
9. Mason CS, Springer CJ, Cooper RG, Superti-Furga G, Marshall CJ, Marais R. Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J. 1999;18:2137–48.
10. Burotto M, Chiou VL, Lee J -M, Kohn EC. The MAPK pathway across different malignancies: a new perspective. Cancer. 2014;120:3446-56.
11. Long GV, Menzies AM, Nagrial AM et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:1239-46.
12. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H et al. Distinctsets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-47.
13. Colombino M, Capone M, Lissia A, Cossu A, Rubino C, De Giorgi V et al. BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol. 2012;30:2522- 9.
14. Fedorenko IV, Gibney GT, Smalley KSM. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene. 2013;32:3009-18.
15. LiuW, Kelly JW, TrivettM et al. D istinct clinical and pathological features are associated with the BRAFT1799A(V600E) mutation in primary melanoma. J Invest Dermatol. 2007;127:900-5.
16. Zebary A, Omholt K, Vassilaki I, et al. KIT, NRAS, BRAF and PTEN mutations in a sample of Swedish patients with acral lentiginous melanoma. J Dermatol Sci. 2013;72:284-9.
17. Chapman PB, Hauschild A, Robert C et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. N Engl Med. 2011;364:2507–16.
18. Yaman B, Akalin T, Kandiloğlu G. Clinicopathological characteristics and mutation profiling in primary cutaneous melanoma: The Am J Dermatopathol. 2015;37:389-97.
19. Akman T, Oztop I, Baskin Y, Akbarpour M, Unal OU, Oflazoglu U et al. The role of BRAF mutation in patients with high-risk malignant melanoma treated with high-dose adjuvant interferon therapy. Med Oncol. 2015;32:440.
20. Yaman B, Kandiloğlu G, Akalin T. BRAF -V600 Mutation heterogeneity in primary and metastatic melanoma: a study with pyrosequencing and immunohistochemistry. Am J Dermatopathol. 2016;38:113-20.
21. Yilmaz I, Gamsizkan M, Kucukodaci Z, Berber U, Demirel D, Haholu A et al. BRAF, KIT, NRAS, GNAQ and GNA11 mutation analysis in cutaneous melanomas in Turkish population. Indian J Pathol Microbiol. 2015;58:279.
22. Sener E, Yildirim P, Tan A, Gokoz O, Tezel GG. Investigation of BRAF mutation analysis with different technical platforms in metastatic melanoma. Pathol-Res Pract. 2019;213:522-30.
23. Can N, Tastekin E, Yalta TD, Sut N, Korkmaz S, Usta U et al. Braf v600 mutation profile of metastatic melanoma in the thrace region of Turkey. Turkish Journal of Pathology. 2018;34:158-164.
24. Clark WH Jr. A classificationof malignant melanoma in man correlated with histogenesis and biologic behavior. Adv Bioi Skin. 1967;8:621-47.
25. Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172:902-8.
26. Landi MT, Bauer J, Pfeiffer RM, Elder DE, Hulley B, Minghetti P et al. MC1R germline variants confer risk for BRAF-mutant melanoma. Science. 2019;313:521- 2.
27. van’t Veer LJ, Burgering BM, Versteeg R, Boot AJ, Ruiter DJ, Osanto S et al. N -ras mutations in human cutaneous melanoma from sun-exposed body sites. Mol Cell Biol. 1989;9:3114-6.
28. Albino AP, Nanus DM, Mentle IR, Cordon-Cardo C, McNutt NS, Bressler J et al. Analysis of ras oncogenes in malignant melanoma and precursor lesions: correlation of point mutations with differentiation phenotype. Oncogene. 1989;4:1363-74.
29. Sheen Y-S, Liao Y-H, Liau J-Y, Lin M-H, Hsieh Y-C, Jee S-H et al. Prevalence of BRAF and NRAS mutations in cutaneous melanoma patients in Taiwan. J Formos Med Assoc 2016;115:121-7.
30. Inumaru JSS, Gordo KIF, Fraga Junior AC, Silva AMTC, Leal CBQS, Ayres FM, et al. Analysis of the BRAF V600E mutation in primary cutaneous melanoma. Genet Mol earch. 2014;13:2840-8.
31. Sakaizawa K, Ashida A, Uchiyama A, Ito T, Fujisawa Y, Ogata D et al. Clinical characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients. J Dermatol Sci. 2015;80:33-7.
32. Heppt MV, Siepmann T, Engel J, Schubert-Fritschle G, Eckel R, Mirlach L et al. Prognostic significance of BRAF and NRAS mutations in melanoma: a German study from routine care. BMC Cancer. 2017;17:536.
33. Libra M, Malaponte G, Navolanic PM, Gangemi P, Bevelacqua V, Proietti L et al. Analysis of BRAF mutation in primary and metastatic melanoma. Cell Cycle. 2005;4:1382-4.
34. Ahmad F, Avabhrath N, Natarajan S, Parikh J, Patole K, Das BR. Molecular evaluation of BRAF V600 mutation and its association with clinicopathological characteristics: First findings from Indian malignant melanoma patients. Cancer Genet. 2019;231-232:46- 53.
35. Ball NJ, Yohn JJ, Morelli JG, Norris DA, Golitz LE, Hoeffler JP. Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol. 1994;102:285-90.
36. van Elsas A, Zerp SF, van der Flier S, Krüse KM, Aarnoudse C, Hayward NK et al. Relevance of ultraviolet-induced N-ras oncogene point mutations in development of primary human cutaneous melanoma. Am J Pathol. 1996;149:883-93.