Молекулярно-генетические особенности меланом слизистых оболочек верхних дыхательных и пищеварительных путей

Игнатова А.В. Молекулярно-генетические особенности меланом слизистых оболочек верхних дыхательных и пищеварительных путей. Современная Онкология. 2016; 18 (4): 42–46.

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Ignatova A.V. Molecular genetic features of the head and neck (upper aerodigestive tract) mucosal melanoma. Journal of Modern Oncology. 2016; 18 (4): 42–46.

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Аннотация

Меланома слизистых оболочек (МСО) – злокачественная опухоль, развивающаяся из меланоцитов. В литературе в основном встречаются немногочисленные ретроспективные исследования и описания отдельных клинических случаев заболевания. Несмотря на единый гистогенез, МСО верхних дыхательных и пищеварительных путей (ВДПП) имеют ряд молекулярно-генетических особенностей, отличных от меланомы кожи. Принимая во внимание множество исследований, посвященных роли прогностических маркеров в развитии опухоли, при МСО ВДПП в клинической практике применяется только несколько маркеров. Частота мутаций в онкогенах BRAF, C-KIT и N-RAS отличается от таковой при меланоме кожи. Для МСО ВДПП характерны относительное увеличение частоты мутаций KIT и N-RAS и снижение частоты мутаций BRAF. В данной статье отражена информация о наиболее изученных молекулярно-генетических маркерах МСО ВДПП и возможностях применения таргетных препаратов. Более детальное понимание патогенеза меланом слизистых оболочек, в особенности молекулярной биологии, поможет определить наиболее эффективные мишени для таргетной терапии.

Ключевые слова: верхние дыхательные и пищеварительные пути, меланома слизистых оболочек, меланома кожи, онкоген, таргетная терапия, сигнальный путь PI3K–AKT–mTOR, RAS/RAF/MEK/ERK, мутации генов BRAF, N-RAS, KIT, ССND1.

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Mucosal melanoma is a rare and aggressive neoplasm of melanocytic origin. To date, in literature only few retrospective series and case reports have been reported on mucosal melanoma. Despite melanoma’s common histological origin,molecular biology of upper aerodigestive tract mucosal melanoma has some specific features compared with those of cutaneous melanomas. Taking into concideration the tremendous number of studies of prognostic molecular markers in cancer, only a few such markers have entered clinical practice in mucosal melanoma. The incidence of activating mutations in the BRAF, C-KIT and N-RAS oncogenes in mucosal melanoma is quite different from cutaneous melanoma: upper aerodigestive tract melanoma is characterized by high incidence of C-KIT and N-RAS mutations, BRAF mutations are uncommon. The most frequently studied markers in upper aerodigestive tract mucosal melanoma and prospectives of targeted therapy are reviewed in this article. A better comprehension of the pathogenesis of disease, in particular its molecular aberrations, can provide important insights into targets for future therapies.

Key words: head and neck, mucosal melanoma, cutaneous melanoma, oncogene,mutation, targeted therapy, signaling pathway PI3K–AKT–mTOR, RAS/RAF/MEK/ERK, mutations BRAF, N-RAS, KIT, ССND1.

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Список литературы

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2. Patel SG, Prasad ML, Escrig M. Primary mucosal malignant melanoma of the head and neck. Head Neck 2002; 24: 247–57.
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7. Lourenço SV, Sangueza M, Sotto MN et al. Primary oral mucosal melanoma: a series of 35 new cases from South America. Am J Dermatopathol 2009; 31: 323–30.
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36. Quintas-Cardama A, Lazar AJ, Woodman SE et al. Complete response of stage IV anal mucosal melanoma expressing KIT Val560Asp to the multikinase inhibitor sorafenib. Nat Clin Pract Oncol 2008; 5 (12): 737–40. DOI: 10.1038/ncponc1251.
37. Woodman SE, Trent JC, Stemke-Hale K et al. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther 2009; 8 (8): 2079–85. DOI: 10.1158/1535-7163. MCT-09-0459.
38. Woodman SE, Davies MA. Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. Biochem Pharmacol 2010; 80 (5): 568–74. DOI: 10.1016/j.bcp.2010.04.032.
39. Zhu YSL, Kong Y, Chi Z et al. Response to sunitinib in Chinese KIT-mutated metastatic mucosal melanoma. J Clin Oncol 2009; 27 (15 s): e20017.
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________________________________________________

1. Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopha-ryngeal melanomas: a clinicopathologic study of 115 cases with a pro-posed staging system. Am J Surg Pathol 2003; 27: 594–611.
2. Patel SG, Prasad ML, Escrig M. Primary mucosal malignant melanoma of the head and neck. Head Neck 2002; 24: 247–57.
3. Owens JM, Roberts DB, Myers JN. The role of postoperative adjuvantradiation therapy in the treatment of mucosal melanomas of the head and neck region. Arch Otolaryngol Head Neck Surg 2003; 129: 864–8.
4. Weber CO. Surgical Experience and Research, in Addition to Interesting Observations from the Surgical Clinic and the Protestant Hospital Bonn. Berlin: G Reimer, 1859; p. 304–5.
5. McLaughlin CC, Wu XC, Jemal A et al. Incidence of noncutaneous melanomas in the US. Cancer 2005; 103: 1000–7.
6. Manolidis S, Donald PJ. Malignant mucosal melanoma of the head and neck: review of the literature and report of 14 patients. Cancer 1997; 80: 1373–86.
7. Lourenço SV, Sangueza M, Sotto MN et al. Primary oral mucosal melanoma: a series of 35 new cases from South America. Am J Dermatopathol 2009; 31: 323–30.
8. Anderson LJ, Berthelsen A, Hansen HS. Malignant melanoma of the upper respiratory tract and the oral cavity. J Otolaryngol 1992; 21: 180–5.
9. Gorsky M, Epstein JB. Melanoma arising from the mucosal surfaces of the head and neck. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998; 86: 715–9.
10. Trap TK, Fu Y, Calcaterra TC. Melanoma of the nasal and paranasal sinus mucosa. Arch Otolaryngol Head Neck Surg 1987; 113: 1086–9.
11. Papaspyrou G, Garbe C, Schadendorf D et al. Mucosal melanomas of the head and neck: new aspects of the clinical outcome, molecular pathology, and treatment with c-kit inhibitors. Melanoma Res 2011; 21: 475–82.
12. Lourenco SV, Fernandes JD, Hsieh R et al. Head and neck mucosal melanoma: a review. Am J Dermatopathol 2014; 36 (7): 578–87. DOI: 10.1097/DAD.0000000000000035.
13. Miller AJ, Mihm MC. Melanoma. N Engl J Med 2006; 355 (1): 51–65.
14. Berger MF, Garraway LA. Applications of genomics in melanoma oncogene discovery. Hematol Oncol Clin North Am 2009; 23 (3): 397–414.
15. Long GV, Menzies AM, Nargial AM et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011; 29 (10): 1239–46.
16. Rajakulendran T, Sahmi M, Lefrançois M et al. A dimerization-dependent mechanism drives RAF catalytic activation. Nature 2009; 461 (7263): 542–5.
17. Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417 (6892): 949–54.
18. Lovly CM, Dablman KB, Fobn LE et al. Routine multiplex mutational profiling of melanomas enables enrollment in genotype – driven therapeutic trials. PLoS One 2012; 7 (4): e35309.
19. Lin K, Baritaki S, Militello L et al. The role of B-RAF mutations in melanoma and the induction of EMT via dysregulation of the NF-KB/Snail/RKIP/PTEN circuit. Genes Cancer 2010; 1 (5): 409–20.
20. Wan PT, Garnett MJ, Roe SM et al. Mechanism of activation of the RAF–ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004; 16 (6): 855–67.
21. Mazurenko N.N. Geneticheskie osobennosti i markery melanomy kozhi. Uspekhi molekuliarnoi onkologii. 2014; 1 (2): 26–35. DOI: 10.17650/2313-805X.2014.1.2.26-35. [in Russian]
22. Turri-Zanoni M, Medicina D, Lombardi D et al. Sinonasal mucosal melanoma: molecular profile and therapeutic implications from a series of 32 cases. Head Neck 2013; 35: 1066–77.
23. Buery RR, Siar CH, Katase N et al. NRAS and BRAF mutation frequency in primary oral mucosal melanoma. Oncol Rep 2011; 26: 783–7.
24. Troussier I, Baglin A-C, Marcy P-Y. Mélanomes muqueux de la tête et du cou état actuel des pratiques et controverses. Bulletin du Cancer.
25. Carvajal RD, Spencer SA, Lydiatt W. Mucosal melanoma: a clinically and biologically unique disease entity. J Natl Compr Cancer Netw JNCCN 2012; 10 (3): 345–56.
26. Beadling C, Jacobson-Dunlop E, Hodi FS et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 2008; 14 (21): 6821–28. DOI: 10.1158/1078-0432.CCR-08-0575.
27. Hauschild A et al. Dabrafenib in BRAF – mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380: 358–65. DOI: 10.1007/s11912-012-0244-x.
28. Kim HS, Kim EK, Jun H et al. Noncutaneous malignant melanoma: a prognostic model from a retrospective multicenter study. BMC Cancer 2010; 10: 167. DOI: 10.1186/1471-2407-10-167.
29. Bartell HL, Bedikian AY, Papadopoulos NE et al. Biochemotherapy in patients with advanced head and neck mucosal melanoma. Head Neck 2008; 30 (12): 1592–8. DOI:10.1002/hed.20910.
30. Mihajlovic M, Vlajkovic S, Jovanovic P, Stefanovic V. Primary mucosal melanomas: a comprehensive review. Int J Clin Exp Pathol 2012; 5 (8): 739–53.
31. Seetharamu N, Ott PA, Pavlick AC. Mucosal melanomas: a case-based review of the literature. Oncologist 2010; 15 (7): 772–81. DOI: 10.1634/theoncologist.2010-0067.
32. Hodi FS, Corless CL, Giobbie-Hurder A et al. Imatinib for melanomas harboring mutationally activated or ampliﬁed KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol 2013; 31 (26): 3182–90. DOI: 10.1200/JCO.2012.47.7836.
33. Guo J, Si L, Kong Y et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or ampliﬁcation. J Clin Oncol 2011; 29 (21): 2904–9. DOI: 10.1200/JCO.2010.33.9275.
34. Lutzky J, Bauer J, Bastian B. Dose-dependent, complete response to imatinib of ametastatic mucosal melanoma with a K642E KIT mutation. Pigm Cell Melanoma Res 2008; 21 (4): 492–3.
35. Postow MA, Luke JJ, Bluth MJ et al. Ipilimumab for patients with advanced mucosal melanoma. Oncologist 2013; 18 (6): 726–32. DOI: 10.1634/theoncologist.2012-0464.
36. Quintas-Cardama A, Lazar AJ, Woodman SE et al. Complete response of stage IV anal mucosal melanoma expressing KIT Val560Asp to the multikinase inhibitor sorafenib. Nat Clin Pract Oncol 2008; 5 (12): 737–40. DOI: 10.1038/ncponc1251.
37. Woodman SE, Trent JC, Stemke-Hale K et al. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther 2009; 8 (8): 2079–85. DOI: 10.1158/1535-7163. MCT-09-0459.
38. Woodman SE, Davies MA. Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. Biochem Pharmacol 2010; 80 (5): 568–74. DOI: 10.1016/j.bcp.2010.04.032.
39. Zhu YSL, Kong Y, Chi Z et al. Response to sunitinib in Chinese KIT-mutated metastatic mucosal melanoma. J Clin Oncol 2009; 27 (15 s): e20017.
40. Ascierto PA, Minor D, Ribas A et al. Trefzer U. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 2013; 31 (26): 3205–11. DOI: 10.1200/JCO.2013.49.8691.
41. Chapman PB, Hauschild A, Robert C et al. Group B-S. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364 (26): 2507–16. DOI: 10.1056/ NEJMoa1103782.
42. Akinleye A, Furqan M, Mukhi N et al. MEK and the inhibitors: from bench to bedside. J Hematol Oncol 2013; 6: 27. DOI: 10.1186/1756-8722-6-27.
43. Voskoboynik M, Arkenau HT. Combination therapies for the treatment of advanced melanoma: a review of current evidence. Biochem Res Int 2014; 2014: 307059. DOI: 10.1155/2014/ 307059.

Авторы

А.В.Игнатова*

ФГБОУ ДПО Российская медицинская академия непрерывного последипломного образования Минздрава России. 123995, Россия, Москва, ул. Баррикадная, д. 2/1
*annasurge@gmail.com

________________________________________________

A.V.Ignatova*

Russian Medical Academy of Postgraduate Education of the Ministry of Health of the Russian Federation. 123995, Russian Federation, Moscow, ul. Barrikadnaya, d. 2/1
*annasurge@gmail.com

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