Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press10010.17650/2313-805X-2017-4-3-35-49REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИThe role of epigenetic factors in the pathogenesis of neurofibromatosis type 1Роль эпигенетических факторов в патогенезе нейрофиброматоза 1-го типаMustafinR. N.МустафинР. Н.
Russian Federation

32 Zaki Validi St., Ufa 450076, Republic of Bashkortostan.

Республика Башкортостан, 450076 Уфа, ул. Заки Валиди, 32.

KhusnutdinovaE. K.ХуснутдиноваЭ. К.
Russian Federation

71 Prospekt Oktyabrya, Ufa 450054, Republic of Bashkortostan.

Республика Башкортостан, 450054 Уфа, проспект Октября, 71.

elzakh@mail.ruBashkir State University.ФГБОУ ВО «Башкирский государственный университет».Bashkir State UniversityФГБОУ ВО «Башкирский государственный университет»Institute of Biochemistry and Genetics, Ufa Science Center, Russian Academy of Sciences.ФГБУН Институт биохимии и генетики Уфимского научного центра РАН.150920174337491610201716102017Copyright ©; 2017, Mustafin R.N., Khusnutdinova E.K.Copyright ©; 2017, Мустафин Р.Н., Хуснутдинова Э.К.2017Mustafin R.N., Khusnutdinova E.K.Мустафин Р.Н., Хуснутдинова Э.К.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/100

The article describes the role of epigenetic processes in the tumorigenesis of neurofibromatosis type 1. The clinical manifestations of neurofibromatosis type 1 is characterized by a pronounced polymorphism erased from with single neurofibromas to severe forms with thousands  of tumors and complications even in patients with the same mutations. More than 1400 mutations in the NF1 gene have been reported, but have not yet identified genotype-phenotype correlations. Detected in the majority of neurofibromas mutation of the second allele of the gene NF1 and loss of heterozygosity may result from common disorders of genome stability and cell cycle regulation. Chance of tissue-specific  inactivation of the second allele is extremely low and can not prove the detection of neurofibromas in most patients with neurofibromatosis type 1. At the same time, the role of epigenetic factors for blocking of oncosupressors has been proven and can be applied to the development  of malignant tumors and neurofibromas. This assumption is proved by the fact that the majority of neurofibromas are formed in puberty, while inheriting the disease from mother to clinical manifestations more severe. This review presents the research on the role of miRNAs and specific methylation in the promoter region of NF1 tumorogenesis in neurofibromatosis type 1. Mutations in the NF1 gene are of great importance in the development of many malignancies. Due to the possibility of pharmacological correction of activity of microRNAs using antisense sequences, the study of epigenetic processes in neurofibromatosis type 1 promising to diagnose and treat not only the disease but also sporadic malignancies.

neurofibromatosis type 1neurofibromintumorogenesisimprintingmicroRNAmethylationCpG-islandsнейрофиброматоз 1-го типанейрофиброминтуморогенезимпринтингмикроРНКметилированиеCpG-островки1. Duong T., Sbidian E., Valeyrie-Allanore L. et al. Mortality associated with neurofibromatosis 1: a cohort study of 1895 patients in 1980–2006 in France. Orphanet J Rare Dis 2011;6:18–26.Duong T., Sbidian E., Valeyrie-Allanore L. et al. Mortality associated with neurofibromatosis 1: a cohort study of 1895 patients in 1980–2006 in France. Orphanet J Rare Dis 2011;6:18–26.2. Gregorian C., Nakashima J., Dry S. et al. PTEN dosage is essential for neurofibroma development and malignant transformation. PNAS 2009;106(46):19479–84.Gregorian C., Nakashima J., Dry S. et al. PTEN dosage is essential for neurofibroma development and malignant transformation. PNAS 2009;106(46):19479–84.3. Melean G., Hernandez A.M., Valero M.C. et al. Monozygotic twins with neurofibromatosis type 1, concordant phenotype and synchronous development of MPNST and metastasis. BMC Cancer 2010;10:407–12.Melean G., Hernandez A.M., Valero M.C. et al. Monozygotic twins with neurofibromatosis type 1, concordant phenotype and synchronous development of MPNST and metastasis. BMC Cancer 2010;10:407–12.4. Ponti G., Losi L., Martotana D. et al. Clinico-pathological and biomolecular findings in Italian patients with multiple cutaneous neurofibromas. Hered Cancer in Clin Pract 2011;9:6–15.Ponti G., Losi L., Martotana D. et al. Clinico-pathological and biomolecular findings in Italian patients with multiple cutaneous neurofibromas. Hered Cancer in Clin Pract 2011;9:6–15.5. Brinkman J., Bron J., Wuisman P. et al. The correlation between clinical, nuclear and histologic findings in a patient with Von Recklinghausen’s disease. World J Surg Oncol 2007;5:130–7.Brinkman J., Bron J., Wuisman P. et al. The correlation between clinical, nuclear and histologic findings in a patient with Von Recklinghausen’s disease. World J Surg Oncol 2007;5:130–7.6. Laycock-van Spyk S., Thomas N., Cooper D., Upadhyaya M. Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and patho genesis. Hum Genomics 2011;5(6): 623–90.Laycock-van Spyk S., Thomas N., Cooper D., Upadhyaya M. Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and patho genesis. Hum Genomics 2011;5(6): 623–90.7. Patil S., Chamberlain R.S. Neoplasms associated with germline and somatic NF1 gene mutations. Oncologist 2012;17(1):101–16.Patil S., Chamberlain R.S. Neoplasms associated with germline and somatic NF1 gene mutations. Oncologist 2012;17(1):101–16.8. Chai G., Liu N., Ma J. et al. MicroRNA10b regulated tumorigenesis in neurofibromatosis type 1. Cancer Sci 2010;101(9):1997–2004.Chai G., Liu N., Ma J. et al. MicroRNA10b regulated tumorigenesis in neurofibromatosis type 1. Cancer Sci 2010;101(9):1997–2004.9. Yap Y.S., McPherson J.R., Ong C. et al. The NF1 gene revisited – from bench to bedside. Oncotarget 2014;5(15); 5873–92.Yap Y.S., McPherson J.R., Ong C. et al. The NF1 gene revisited – from bench to bedside. Oncotarget 2014;5(15); 5873–92.10. Vandenbrucke I. Identification and characterization of neurofibromatosis type 1 splice variants. 2004.Vandenbrucke I. Identification and characterization of neurofibromatosis type 1 splice variants. 2004.11. Дрозд О.В., Бабенко О.В., Семячкина А.Н. и др. Разработка подходов к ДНКдиагностике нейрофиброматоза 1-го типа в России. Медицинская генетика 2005;4(7):322–6. [Drozd O.V., Babenko O.V., Semyachkina A.N. et al. Development of approaches to DNA diagnostics of type 1 neurofibromatosis in Russia. Meditsinskaya genetika = Medical Genetics 2005;4(7):322–6. (In Russ.)].Дрозд О.В., Бабенко О.В., Семячкина А.Н. и др. Разработка подходов к ДНКдиагностике нейрофиброматоза 1-го типа в России. Медицинская генетика 2005;4(7):322–6. [Drozd O.V., Babenko O.V., Semyachkina A.N. et al. Development of approaches to DNA diagnostics of type 1 neurofibromatosis in Russia. Meditsinskaya genetika = Medical Genetics 2005;4(7):322–6. (In Russ.)].12. Мустафин Р .Н., Бермишева М.А., Хуснутдинова Э.К. Особенности нейрофиброматоза 1-го типа в Республике Башкортостан. Медицинская генетика 2015;14(6): 29–35. [Mustafin R.N., Bermisheva M.A., Khusnutdinova E.K. Features of type 1 neurofibromatosis in the Republic of Bashkortostan. Meditsinskaya genetika = Medical Genetics 2015;14(6):29–35. (In Russ.)].Мустафин Р .Н., Бермишева М.А., Хуснутдинова Э.К. Особенности нейрофиброматоза 1-го типа в Республике Башкортостан. Медицинская генетика 2015;14(6): 29–35. [Mustafin R.N., Bermisheva M.A., Khusnutdinova E.K. Features of type 1 neurofibromatosis in the Republic of Bashkortostan. Meditsinskaya genetika = Medical Genetics 2015;14(6):29–35. (In Russ.)].13. Ratner N., Miller S.J. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat RevCancer 2015;15(5):290–301.Ratner N., Miller S.J. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat RevCancer 2015;15(5):290–301.14. Sabbagh A., Pasmant E., Laurendeau I. et al. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Gen 2009;18(18): 2768–78.Sabbagh A., Pasmant E., Laurendeau I. et al. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Gen 2009;18(18): 2768–78.15. Eisenbarth I., Beyer K., Krone W., Assum G. Toward a survey of somatic mutation of the NF1 gene in benigh neurofibromas of patients with neurofibromatoss type 1. Am J Hum Genet 2000;66(2):393–401.Eisenbarth I., Beyer K., Krone W., Assum G. Toward a survey of somatic mutation of the NF1 gene in benigh neurofibromas of patients with neurofibromatoss type 1. Am J Hum Genet 2000;66(2):393–401.16. Stevenson D.A., Zhou H., Ashrafi S. et al. Double inactivation of NF1 in tibial pseudarthrosis. Am J Hum Genet 2006;79(1):143–8.Stevenson D.A., Zhou H., Ashrafi S. et al. Double inactivation of NF1 in tibial pseudarthrosis. Am J Hum Genet 2006;79(1):143–8.17. Boyd K.P., Korf B.R., Theos A. Neurofibromatosis type 1. J Am Acad Dermatol 2009;61(1):1–16.Boyd K.P., Korf B.R., Theos A. Neurofibromatosis type 1. J Am Acad Dermatol 2009;61(1):1–16.18. MсGillicuddy L.T., Fromm J.A., Hollstein P.E. Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 2009;16(1):44–54.MсGillicuddy L.T., Fromm J.A., Hollstein P.E. Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 2009;16(1):44–54.19. Gutmann D.H., Giovannini M. Mouse models of neurofibromatosis 1 and 2. Neoplasia 2002;4(4):279–90.Gutmann D.H., Giovannini M. Mouse models of neurofibromatosis 1 and 2. Neoplasia 2002;4(4):279–90.20. Hawes J.J., Tuskan R.G., Reilly K.M. Nf1 expression is dependent on strain background: implications for tumor suppressor haploinsufficiency studies. Neurogenetics 2007;8(2):121–30.Hawes J.J., Tuskan R.G., Reilly K.M. Nf1 expression is dependent on strain background: implications for tumor suppressor haploinsufficiency studies. Neurogenetics 2007;8(2):121–30.21. Jouhilahti E.M., Peltonen S., Heape A.M., Peltonen J. The pathoetiology of neurofibromatosis 1. Am J Pathol 2011;178(5):1932–9.Jouhilahti E.M., Peltonen S., Heape A.M., Peltonen J. The pathoetiology of neurofibromatosis 1. Am J Pathol 2011;178(5):1932–9.22. Huppi K., Volfovsky N., Mackiewicz M. et al. MicroRNAs and genomic instability. Semin Cancer Biol 2007;17(1):65–73.Huppi K., Volfovsky N., Mackiewicz M. et al. MicroRNAs and genomic instability. Semin Cancer Biol 2007;17(1):65–73.23. Bottillo I., Luca A., Schirinzi A. et al. Functional analysis of splicing mutations in exon 7 of NF1 gene. BMC Med Genet 2007;8:4–13.Bottillo I., Luca A., Schirinzi A. et al. Functional analysis of splicing mutations in exon 7 of NF1 gene. BMC Med Genet 2007;8:4–13.24. Zhou H., Hinman M., Barron V. et al. Hu proteins regulate alternative splicing by inducing localized histone hyperacetylation in an RNA-dependent manner. PNAS 2007;108(36):627–35.Zhou H., Hinman M., Barron V. et al. Hu proteins regulate alternative splicing by inducing localized histone hyperacetylation in an RNA-dependent manner. PNAS 2007;108(36):627–35.25. Горбунова В.Н., Имянитов Е.Н., Ледащева Т .А. и др. Молекулярная неврология. Часть III. Опухоли головного мозга, онкогены и антионкогены. Под ред. А.А. Скоромца. СПб.: Интермедика, 2004. С. 219–232. [Gorbunova V.N., Imyanitov E.N., Ledashcheva Т .А. et al. Molecular neurology. Part III. Tumors of the brain, oncogenes and anti-oncogenes. Ed. A.A. Skoromets. Saint Petersburg: Intermedika, 2004. Pp. 219–232. (In Russ.)].Горбунова В.Н., Имянитов Е.Н., Ледащева Т .А. и др. Молекулярная неврология. Часть III. Опухоли головного мозга, онкогены и антионкогены. Под ред. А.А. Скоромца. СПб.: Интермедика, 2004. С. 219–232. [Gorbunova V.N., Imyanitov E.N., Ledashcheva Т .А. et al. Molecular neurology. Part III. Tumors of the brain, oncogenes and anti-oncogenes. Ed. A.A. Skoromets. Saint Petersburg: Intermedika, 2004. Pp. 219–232. (In Russ.)].26. Wimmer K., Callens T., Wernstedt A., Messiaen L. The NF1 gene contains hotspots for L1 endonuclease-dependent de novo insertion. PLoS Genet 2011;7(11):e1002371.Wimmer K., Callens T., Wernstedt A., Messiaen L. The NF1 gene contains hotspots for L1 endonuclease-dependent de novo insertion. PLoS Genet 2011;7(11):e1002371.27. Ayarpadikannan S., Lee H.E., Han K., Kim H.S. Transposable element-driven transcript diversification and its relevance to genetic disorders. Gene 2015;558(2):187–94.Ayarpadikannan S., Lee H.E., Han K., Kim H.S. Transposable element-driven transcript diversification and its relevance to genetic disorders. Gene 2015;558(2):187–94.28. Патрушев Л.И., Минкевич И.Г. Проблема размера геномов эукариот. Успехи биологической химии 2007;47:293–370. [Patrushev L.I., Minkevich I.G. The problem of the size of the genomes of eukaryotes. Uspekhi biologicheskoy khimii = Advances in Biological Chemistry 2007;47:293–370. (In Russ.)].Патрушев Л.И., Минкевич И.Г. Проблема размера геномов эукариот. Успехи биологической химии 2007;47:293–370. [Patrushev L.I., Minkevich I.G. The problem of the size of the genomes of eukaryotes. Uspekhi biologicheskoy khimii = Advances in Biological Chemistry 2007;47:293–370. (In Russ.)].29. Козлов В.А. Метилирование ДНК клетки и патология организма. Медицинская иммунология 2008;10(4): 307–18. [Kozlov V.A. Methylation of cell DNA and pathology of the body. Meditsinskaya immunologiya = Medical Immunology 2008;10(4):307–18. (In Russ.)].Козлов В.А. Метилирование ДНК клетки и патология организма. Медицинская иммунология 2008;10(4): 307–18. [Kozlov V.A. Methylation of cell DNA and pathology of the body. Meditsinskaya immunologiya = Medical Immunology 2008;10(4):307–18. (In Russ.)].30. Jeong S.Y., Park S.J., Kim H.J. The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. J Korean Med Sci 2006;21(1):107–12.Jeong S.Y., Park S.J., Kim H.J. The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. J Korean Med Sci 2006;21(1):107–12.31. Fishbein L., Eady B., Sanek N. et al. Analysis of somatic NF1 promoter methylation plexiform neurofibromas and Schwann cells. Cancer Genet Cytogenet 2005;157(2):181–6.Fishbein L., Eady B., Sanek N. et al. Analysis of somatic NF1 promoter methylation plexiform neurofibromas and Schwann cells. Cancer Genet Cytogenet 2005;157(2):181–6.32. Garcia-Linares C., Fernandez-Rodriguez J., Terribas E. et al. Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: importance of copy neutral LOH. Hum Mutat 2011;32(1):78–90.Garcia-Linares C., Fernandez-Rodriguez J., Terribas E. et al. Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: importance of copy neutral LOH. Hum Mutat 2011;32(1):78–90.33. De Raedt T.D., Maertens O., Chmara M. et al. Somatic loss of wild type NF1 allele in neurofibromas: comparison of NF1 microdeletion and non-microdeletion patients. Genes Chromosomes Cancer 2006;45(10):893–904.De Raedt T.D., Maertens O., Chmara M. et al. Somatic loss of wild type NF1 allele in neurofibromas: comparison of NF1 microdeletion and non-microdeletion patients. Genes Chromosomes Cancer 2006;45(10):893–904.34. Stewart D.R., Pemov A., van Loo P. et al. Mitotic recombination of chromosome arm 17q as a cause of loss of heterozygosity of NF1 in neurofibromatosis type 1-asso ciated glomus tumors. Genes Chromosomes Cancer 2012;51(5):429–37.Stewart D.R., Pemov A., van Loo P. et al. Mitotic recombination of chromosome arm 17q as a cause of loss of heterozygosity of NF1 in neurofibromatosis type 1-asso ciated glomus tumors. Genes Chromosomes Cancer 2012;51(5):429–37.35. Geller M., Ribeiro M.G., Araújo A.P. et al. Serum IgE levels in neurofibromatosis 1. Int J Immunogenet 2006;33(2):111–5.Geller M., Ribeiro M.G., Araújo A.P. et al. Serum IgE levels in neurofibromatosis 1. Int J Immunogenet 2006;33(2):111–5.36. Chen S., Burgin S., McDaniel A. et al. NF1–/– schwann cell-conditioned medium modulates mast cell degranulation by c-Kit-mediated hyperactivation of phosphatidylinositol 3-kinase. Am J Pathol 2010;177(6):3125–32.Chen S., Burgin S., McDaniel A. et al. NF1–/– schwann cell-conditioned medium modulates mast cell degranulation by c-Kit-mediated hyperactivation of phosphatidylinositol 3-kinase. Am J Pathol 2010;177(6):3125–32.37. Horvath S. DNA methylation age of human tissues and cell types. Genome 2013;14(10):115.Horvath S. DNA methylation age of human tissues and cell types. Genome 2013;14(10):115.38. Nissan M.H., Pratilas C.A., Jones A.M. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res 2014;74(8):2340–50.Nissan M.H., Pratilas C.A., Jones A.M. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res 2014;74(8):2340–50.39. Holzel M., Huang S., Koster J. et al. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell 2010;142(2): 218–29.Holzel M., Huang S., Koster J. et al. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell 2010;142(2): 218–29.40. Рунов А.Л., Вонский М.С., Михельсон В.М. Уровень метилирования ДНК и длина теломер как основа для построения модели биологических часов старения. Цитология 2015;57(3):192–6. [Runov A.L., Vonskiy M.S., Mikhel’son V.М. The level of DNA methylation and the length of telomeres as a basis for constructing a model of biological aging hours. Tsitologiya = Cytology 2015;57(3):192–6. (In Russ.)].Рунов А.Л., Вонский М.С., Михельсон В.М. Уровень метилирования ДНК и длина теломер как основа для построения модели биологических часов старения. Цитология 2015;57(3):192–6. [Runov A.L., Vonskiy M.S., Mikhel’son V.М. The level of DNA methylation and the length of telomeres as a basis for constructing a model of biological aging hours. Tsitologiya = Cytology 2015;57(3):192–6. (In Russ.)].41. Ванюшин Б.Ф. Эпигенетика сегодня и завтра. Вавиловский журнал генетики и селекции 2013;17(4/2):805–32. [Vanyushin B.F. Epigenetics today and tomorrow. Vavilovskiy zhurnal genetiki i selektsii = Vavilov Journal of Genetics and Breeding 2013;17(4/2):805–32. (In Russ.)].Ванюшин Б.Ф. Эпигенетика сегодня и завтра. Вавиловский журнал генетики и селекции 2013;17(4/2):805–32. [Vanyushin B.F. Epigenetics today and tomorrow. Vavilovskiy zhurnal genetiki i selektsii = Vavilov Journal of Genetics and Breeding 2013;17(4/2):805–32. (In Russ.)].42. Horan M.P., Cooper D.N., Upadhyaya M. Hypermethylation of the neurofibromatosis type 1 (NF1) gene promoter is not a common event in the inactivation of the NF1 gene in NF1-specific tumours. Hum Genet 2000;107(1):33–9.Horan M.P., Cooper D.N., Upadhyaya M. Hypermethylation of the neurofibromatosis type 1 (NF1) gene promoter is not a common event in the inactivation of the NF1 gene in NF1-specific tumours. Hum Genet 2000;107(1):33–9.43. Harder A., Rosche M., Reuss D.E. et al. Methylation analysis of the neurofibromatosis type 1 (NF1) promoter in peripheral nerve sheath tumors. Eur J Cancer 2004;40(18):2820–8.Harder A., Rosche M., Reuss D.E. et al. Methylation analysis of the neurofibromatosis type 1 (NF1) promoter in peripheral nerve sheath tumors. Eur J Cancer 2004;40(18):2820–8.44. Gutmann D.H., McLellan M.D., Hussain I. et al. Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma. Genome Res 2013;23(3):431–9.Gutmann D.H., McLellan M.D., Hussain I. et al. Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma. Genome Res 2013;23(3):431–9.45. Calin G.A., Dumitru C.D., Shimizu M. et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002;99(24):15524–9.Calin G.A., Dumitru C.D., Shimizu M. et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002;99(24):15524–9.46. Gozuacik D., Akkoc Y., Ozturk D.G., Kocak M. Autophagy-regulating microRNAs and cancer. Front Oncol 2017;7:65.Gozuacik D., Akkoc Y., Ozturk D.G., Kocak M. Autophagy-regulating microRNAs and cancer. Front Oncol 2017;7:65.47. Sedani A., Cooper D.N., Upadhyaya M. An emerging role for microRNAs in NF1 tumorigenesis. Human Genomics 2012;6:23–32.Sedani A., Cooper D.N., Upadhyaya M. An emerging role for microRNAs in NF1 tumorigenesis. Human Genomics 2012;6:23–32.48. Garcia-Orti L., Cristobal I., Cirauqui C. et al. Integration of SNP and mRNA arrays with microRNA profiling reveals that miR-370 is upregulated and targets NF1 in acute myeloid leukemia. PLoS One 2012;7(10):e47717.Garcia-Orti L., Cristobal I., Cirauqui C. et al. Integration of SNP and mRNA arrays with microRNA profiling reveals that miR-370 is upregulated and targets NF1 in acute myeloid leukemia. PLoS One 2012;7(10):e47717.49. Paschou M., Doxakis E. Neurofibromin 1 is a miRNA target in neurons. PLoS One 2012;7(10):e46773.Paschou M., Doxakis E. Neurofibromin 1 is a miRNA target in neurons. PLoS One 2012;7(10):e46773.50. Stark M.S., Bonazzi V.F., Boyle G.M. et al. MiR-514a regulates the tumour suppressor NF1 and modulates BRAFi sensitivity in melanoma. Oncotarget 2015;6(19):17753–63.Stark M.S., Bonazzi V.F., Boyle G.M. et al. MiR-514a regulates the tumour suppressor NF1 and modulates BRAFi sensitivity in melanoma. Oncotarget 2015;6(19):17753–63.51. Ling H., Fabbri M., Calin G.A. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 2013;12(11): 847–65.Ling H., Fabbri M., Calin G.A. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 2013;12(11): 847–65.52. Pasmant E., Sabbagh A., Masliah-Planchon J. et al. Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J Natl Cancer Inst 2011;103(22):1713–22.Pasmant E., Sabbagh A., Masliah-Planchon J. et al. Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J Natl Cancer Inst 2011;103(22):1713–22.53. Mubotter T., Kluwe L., Hogel J. et al. Non-coding RNA ANRIL and the number of plexiform neurofibromas in patients with NF1 microdeletions. BMC Med Genet 2012;13:98.Mubotter T., Kluwe L., Hogel J. et al. Non-coding RNA ANRIL and the number of plexiform neurofibromas in patients with NF1 microdeletions. BMC Med Genet 2012;13:98.54. Li Z., Yu X., Shen J. ANRIL: a pivotal tumor suppressor long non-coding RNA in human cancers. Tumour Biol 2016;37(5):5657–61.Li Z., Yu X., Shen J. ANRIL: a pivotal tumor suppressor long non-coding RNA in human cancers. Tumour Biol 2016;37(5):5657–61.