МОЛЕКУЛЯРНАЯ БИОЛОГИЯ ГЛИОМ НИЗКОЙ СТЕПЕНИ ЗЛОКАЧЕСТВЕННОСТИ У ДЕТЕЙ

DOI: https://doi.org/None

К.Е. Борисов, кандидат медицинских наук, Д.Д. Сакаева, доктор медицинских наук ГУЗ Республиканский клинический онкологический диспансер Минздрава Республики Башкортостан, 450054, Российская Федерация, Уфа, проспект Октября, 73/1 E-mail: [email protected]

В литературном обзоре рассмотрены вопросы молекулярной биологии глиом низкой степени злокачественности у детей и подростков. Представлены данные о характерных генных аберрациях при пилоцитарной астроцитоме, плеоморфной ксантоастроцитоме, субэпендимарной гигантоклеточной астроцитоме и ганглиоглиоме, о частоте и прогностической значимости различных мутаций. У младенцев до 1 года частота глиом низкой степени злокачественности составляет 67%, локализуются они обычно в больших полушариях; у детей от 1 года до 5 лет – соответственно 86% при преимущественно инфратенториальной локализации. Дупликация гена BRAF на хромосоме 7q34 характерна для пилоцитарной астроцитомы и в большинстве случаев ассоциирована с благоприятным прогнозом. Активирующие мутации BRAF более характерны для плеоморфной ксантоастроцитомы, ганглиоглиомы и пилоцитарной астроцитомы с внемозжечковой локализацией и обладают негативной прогностической значимостью. Ведущим звеном патогенеза субэпендимарной гигантоклеточной астроцитомы является нарушение в mTORсигнальном каскаде. Исследование генетических изменений при глиомах у детей может содействовать разработке новых подходов в лечении, направленных на молекулярные мишени, что способствует индивидуализации противоопухолевой терапии.
Ключевые слова: 
глиомы низкой степени злокачественности, дети, молекулярная биология
Для цитирования: 
Борисов К.Е., Сакаева Д.Д. МОЛЕКУЛЯРНАЯ БИОЛОГИЯ ГЛИОМ НИЗКОЙ СТЕПЕНИ ЗЛОКАЧЕСТВЕННОСТИ У ДЕТЕЙ. Молекулярная медицина, 2016; (3): -

Список литературы: 
  1. Qaddoumi I., Sultan I., Gajjar A. Outcome and prognostic features in pediatric gliomas: a review of 6212 cases from the surveillance, epidemiology and end results (SEER) database. Cancer. 2009; 115 (24): 5761–70.
  2. Rozen W.M., Joseph S., Lo P.A. Spontaneous regression of low-grade gliomas in pediatric patients without neurofibromatosis. Pediatr. Neurosurg. 2008; 44 (4): 324–8.
  3. Tabori U., Vukovic B., Zielenska M., Hawkins C., Braude I., Rutka J., Bouffet E., Squire J., Malkin D. The role of telomere maintenance in the spontaneous growth arrest of pediatric low-grade gliomas. Neoplasia. 2006; 8 (2): 136–42.
  4. Rickert C.H., Paulus W. Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification. Childs. Nerv. Syst. 2001; 17 (9): 503–11.
  5. Pfister S., Janzarik W.G., Remke M., Ernst A., Werft W., Becker N., Toedt G., Wittmann A., Kratz C., Olbrich H., Ahmadi R., Thieme B., Joos S., Radlwimmer B., Kulozik A., Pietsch T., Herold-Mende C., Gnekow A., Reifenberger G., Korshunov A., Scheurlen W., Omran H., Lichter P. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J. Clin. Invest. 2008; 118 (5): 1739–49.
  6. Dimitriadis E., Alexiou G.A., Tsotsou P., Simeonidi E., Stefanaki K., Patereli A., Prodromou N., Pandis N. BRAF alterations in pediatric low grade gliomas and mixed neuronal-glial tumors. J. Neurooncol. 2013; 113 (3): 353–8.
  7. Dahiya S., Yu J., Kaul A., Leonard J.R., Gutmann D.H. Novel BRAF Alteration in a Sporadic Pilocytic Astrocytoma. Case Report Med. 2012; 2012: Article ID 418672.
  8. Lin A., Rodriguez F.J., Karajannis M.A., Williams S.C., Legault G., Zagzag D., Burger P.C., Allen J.C., Eberhart C.G., Bar E.E. BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants. J. Neuropathol. Exp. Neurol. 2012; 71 (1): 66–72.
  9. Cin H., Meyer C., Herr R., Janzarik W.G., Lambert S., Jones D.T., Jacob K., Benner A., Witt H., Remke M., Bender S., Falkenstein F., Van Anh T.N., Olbrich H., von Deimling A., Pekrun A., Kulozik A.E., Gnekow A., Scheurlen W., Witt O., Omran H., Jabado N., Collins V.P., Brummer T., Marschalek R., Lichter P., Korshunov A., Pfister S.M. Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol. 2011; 121 (6): 763–74.
  10. Jacob K., Albrecht S., Sollier C., Faury D., Sader E., Montpetit A., Serre D., Hauser P., Garami M., Bognar L., Hanzely Z., Montes J.L., Atkinson J., Farmer J.P., Bouffet E., Hawkins C., Tabori U., Jabado N. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumors. Br. J. Cancer. 2009; 101 (4): 722–33.
  11. Schindler G., Capper D., Meyer J., Janzarik W., Omran H., Herold-Mende C., Schmieder K., Wesseling P., Mawrin C., Hasselblatt M., Louis D.N., Korshunov A., Pfister S., Hartmann C., Paulus W., Reifenberger G., von Deimling A. Analysis of BRAF V600E mutation in 1320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011; 121 (3): 397–405.
  12. Jones D.T.W., Kocialkowski S., Liu L., Pearson D.M., Ichimura K., Collins V.P. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene. 2009; 28 (20): 2119–23.
  13. Tibbetts K.M., Emnett R.J., Gao F., Perry A., Gutmann D.H., Leonard J.R. Histopathologic predictors of pilocytic astrocytoma event-free survival. Acta Neuropathol. 2009; 117 (6): 657–65.
  14. Horbinski C., Hamilton R.L., Nikiforov Y., Pollack I.F. Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol. 2010; 119 (5): 641–9.
  15. Horbinski C., Nikiforova M.N., Hagenkord J.M., Hamilton R.L., Pollack I.F. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol. 2012; 14 (6): 777–89.
  16. Hawkins C.E., Walker E., Mohamed N., Zhang C., Jacob K., Shirinian M., Alon N., Kahn D., Fried I., Scheinemann K., Tsangaris E., Dirks P., Tressler R., Bouffet E., Jabado N., Tabori U. BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low grade astrocytoma. Clin. Cancer Res. 2011; 17 (14): 4790–8.
  17. Courtois-Cox S., Genther Williams S.M., Reszek E.E., Johnson B.W., McGillicuddy L.T., Johannessen C.M., Hollstein P.E., MacCollin M., Cichowski K. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 2006; 10 (6): 459–72.
  18. Mueller S., Phillips J., Onar-Thomas A., Romero E., Zheng S., Wiencke J.K., McBride S.M., Cowdrey C., Prados M.D., Weiss W.A., Berger M.S., Gupta N., Haas-Kogan D.A. PTEN promoter methylation and activation of the PI3K/Akt/mTOR pathway in pediatric gliomas and influence on clinical outcome. Neuro Oncol. 2012; 14 (9): 1146–52.
  19. Ohgaki H., Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am. J. Pathol. 2007; 170 (5): 1445–53.
  20. Rodriguez E.F., Scheithauer B.W., Giannini C., Rynearson A., Cen L., Hoesley B., Gilmer-Flynn H., Sarkaria J.N., Jenkins S., Long J., Rodriguez F.J. PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma. Acta Neuropathol. 2011; 121 (3): 407–20.
  21. McBride S., Perez D., Polley M., Vandenberg S.R., Smith J.S., Zheng S., Lamborn K.R., Wiencke J.K., Chang S.M., Prados M.D., Berger M.S., Stokoe D., Haas-Kogan D.A. Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patients survival. J. Neurooncol. 2010; 97 (1): 33–40.
  22. Sharma M.K., Watson M.A., Lyman M., Perry A., Aldape K.D., Deák F., Gutmann D.H. Matrilin-2 expression distinguishes clinically relevant subsets of pilocytic astrocytoma. Neurology. 2006; 66 (1): 127–30.
  23. Wong K., Chang Y., Tsang Y.T.M., Perlaky L., Su J., Adesina A., Armstrong D.L., Bhattacharjee M., Dauser R., Blaney S.M., Chintagumpala M., Lau C.C. Expression Analysis of Juvenile Pilocytic Astrocytomas by Oligonucleotide Microarray Reveals Two Potential Subgroups. Cancer Res. 2005; 65 (1): 76–84.
  24. Kluwe L., Hagel C., Tatagiba M., Thomas S., Stavrou D., Ostertag H., von Deimling A., Mautner V.F. Loss of NF1 alleles distinguish sporadic from NF1-associated pilocytic astrocytomas. J. Neuropathol. Exp. Neurol. 2001; 60 (9): 917–20.
  25. Tihan T., Fisher P.G., Kepner J.L., Godfraind C., McComb R.D., Goldthwaite P.T., Burger P.C. Pediatric astrocytomas with monomorphous pilomixoid features and a less favorable outcome. J. Neuropathol. Exp. Neurol. 1999; 58 (10): 1061–8.
  26. Komotar R.J., Burger P.C., Carson B.S., Brem H., Olivi A., Goldthwaite P.T., Tihan T. Pilocytic and pilomixoid hypothalamic/chiasmatic astrocytomas. Neurosurgery. 2004; 54 (1): 72–9.
  27. Dias-Santagata D., Lam Q., Vernovsky K., Vena N., Lennerz J.K., Borger D.R., Batchelor T.T., Ligon K.L., Iafrate A.J., Ligon A.H., Louis D.N., Santagata S. BRAF V600E mutations are common in pleomorphic xantoastrocytoma: diagnostic and therapeutic implications. PLoS One. 2011; 6 (3): e17948.
  28. Giannini C., Scheithauer B.W., Burger P.C., Brat D.J., Wollan P.C., Lach B., O’Neill B.P. Pleomorphic xantoastrocytoma: what do we really know about it? Cancer. 1999; 85 (9): 2033–45.
  29. Lim S., Kim J.H., Kim S.A., Park E.S., Ra Y.S., Kim C.J. Prognostic Factors and Therapeutic Outcomes in 22 Patients with Pleomorphic Xantoastrocytoma. J. Korean Neurosurg. Soc. 2013; 53 (5): 281–7.
  30. Pahapill P.A., Ramsay D.A., Del Maestro R.F. Pleomorphic xantoastrocytoma: case report and analysis of the literature concerning the efficacy of resection and the significance of necrosis. Neurosurgery. 1996; 38 (4): 822–8.
  31. Giannini C., Scheithauer B.W., Lopes M.B., Hirose T., Kros J.M., VandenBerg S.R. Immunophenotype of pleomorphic xantoastrocytoma. Am. J. Surg. Pathol. 2002; 26 (4): 479–85.
  32. Giannini C., Hebrink D., Scheithauer B.W., Dei Tos A.P., James C.D. Analysis of p53 mutation and expression in pleomorphic xantoastrocytoma. Neurogenetics. 2001; 3 (3): 159–62.
  33. Weber R.G., Hoischen A., Ehrler M., Zipper P., Kaulich K., Blaschke B., Becker A.J., Weber-Mangal S., Jauch A., Radlwimmer B., Schramm J., Wiestler O.D., Lichter P., Reifenberger G. Frequent loss of chromosome 9, homozygous CDKN2A/p14(ARF)/CDKN2B deletion and low TSC1 mRNA expression in pleomorphic xantoastrocytoma. Oncogene. 2007; 26 (7): 1088–97.
  34. Marucci G., Morandi L. Assessment of MGMT promoter methylation status in pleomorphic xantoastrocytoma. J. Neurooncol. 2011; 105 (2): 397–400.
  35. Gallo P., Cecchi P.C., Locatelli F., Rizzo P., Ghimenton C., Gerosa M., Pinna G. Pleomorphic xantoastrocytoma: Long-term results of surgical treatment and analysis of prognostic factors. Br. J. Neurosurg. 2013; 759–64.
  36. Koga T., Morita A., Maruyama K., Tanaka M., Ino Y., Shibahara J., Louis D.N., Reifenberger G., Itami J., Hara R., Saito N., Todo T. Long-term control of disseminated pleomorphic xantoastrocytoma with anaplastic features by means of stereotactic irradiation. Neuro Oncol. 2009; 11 (4): 446–51.
  37. Chamberlain M.C. Salvage therapy with BRAF inhibitors for recurrent pleomorphic xanthoastrocytoma: a retrospective case series. J. Neurooncol. 2013; 114 (2): 237–40.
  38. Devlin L.A., Shepherd C.H., Crawford H., Morrison P.J. Tuberous sclerosis complex: clinical features, diagnosis, and prevalence within Northern Ireland. Develop. Med. Child. Neurol. 2006; 48 (6): 495–9.
  39. Hallet L., Foster T., Liu Z., Blieden M., Valentim J. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestation: systematic review. Curr. Med. Res. Opin. 2011; 27 (8): 1571–83.
  40. Zhou J., Shrikhande G., Xu J., McKay R.M., Burns D.K., Johnson J.E., Parada L.F. Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes Dev. 2011; 25 (15): 1595–600.
  41. Napolioni V., Moavero R., Curatolo P. Recent advances in neurobiology of Tuberous Sclerosis Complex. Brain Develop. 2009; 14 (2): 104–13.
  42. Krueger D.A., Care M.M., Agricola K., Tudor C., Mays M., Franz D.N. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology. 2013; 80 (6): 574–80.
  43. Franz D.N., Belousova E., Sparagana S., Bebin E.M., Frost M., Kuperman R., Witt O., Kohrman M.H., Flamini J.R., Wu J.Y., Curatolo P., de Vries P.J., Whittemore V.H., Thiele E.A., Ford J.P., Shah G., Cauwel H., Lebwohl D., Sahmoud T., Jozwiak S. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomized, placebo-controlled phase 3 study. Lancet. 2013; 381 (9861): 125–32.
  44. Amin S., Carter M., Edwards R.J., Pople I., Aquilina K., Merrifield J., Osborne J.P., O’Callaghan F.J. The outcome of surgical management of subependymal giant cell astrocytoma in tuberous sclerosis complex. Eur. J. Paediatr. Neurol. 2013; 17 (1): 36–44.
  45. Giulioni M., Galassi E., Zucchelli M., Volpi L. Seizure outcome of lesionectomy in glioneuronal tumors associated with epilepsy in children. J. Neurosurg. 2005; 102 (3): 288–93.
  46. Brainer-Lima P.T., Brainer-Lima A.M., Azevedo-Filho H.R. Ganglioglioma: comparison with other low-grade brain tumors. Arq. Neuropsiquiatr. 2006; 64 (3A): 613–8.
  47. Luyken C., Blumcke I., Fimmers R., Urbach H., Wiestler O.D., Schramm J. Supratentorial gangliogliomas: histopathologic grading and tumor recurrence in 184 patients with median follow-up of 8 years. Cancer. 2004; 101 (1): 146–55.
  48. Compton J.J., Laack N.N., Eckel L.J., Schomas D.A., Giannini C., Meyer F.B. Long-term outcomes for low-grade intracranial ganglioglioma: 30-year experience from the Mayo Clinic. J. Neurosurg. 2012; 117 (5): 825–30.
  49. Hoischen A., Ehrler M., Fassunke J., Simon M., Baudis M., Landwehr C., Radlwimmer B., Lichter P., Schramm J., Becker A.J., Weber R.G. Comprehensive characterization of genomic aberrations in gangliogliomas by CGH, array-based CGH and interphase FISH. Brain Pathol. 2008; 18 (3): 326–37.
  50. Pandita A., Balasubramaniam A., Perrin R., Shannon P., Guha A. Malignant and benign ganglioglioma: a pathological and molecular study. Neuro Oncol. 2007; 9 (2): 124–34.
  51. Horbinski C., Kofler J., Yeaney G., Camelo-Piragua S., Venneti S., Louis D.N., Perry A., Murdoch G., Nikiforova M. Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. Brain Pathol. 2011; 21 (5): 564–74.
  52. Dougherty M.J., Santi M., Brose M.S., Ma C., Resnick A.C., Sievert A.J., Storm P.B., Biegel J.A. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro-Oncol. 2010; 12 (7): 621–30.
  53. Dahiya S., Haydon D.H., Alvarado D., Gurnett C.A., Gutmann D.H., Leonard J.R. BRAF(V600E) mutation is negative prognosticator in pediatric ganglioglioma. Acta Neuropathol. 2013; 125 (6): 901–10.