Pathological and molecular advances in pediatric low-grade astrocytoma

Annual Review of Pathology: Mechanisms of Disease

Volumn 8, Issue , 2013, Pages 361-379

  Rodriguez, Fausto J ^a   Lim, Kah Suan ^a   Bowers, Daniel ^b   Eberhart, Charles G ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

BRAF; NF1; Pilocytic astrocytoma; RAF1

Indexed keywords

ERLOTINIB; MITOGEN ACTIVATED PROTEIN KINASE; RAPAMYCIN; SORAFENIB;

ASTROCYTOMA; BRAIN CORTEX; CHROMOSOME 7Q; CLINICAL FEATURE; COMPARATIVE GENOMIC HYBRIDIZATION; CYTOGENETICS; DIAGNOSTIC VALUE; DNA DAMAGE; DNA SEQUENCE; GENE DUPLICATION; GENE EXPRESSION; GENE MAPPING; GLIOMA; GROWTH DISORDER; HISTOGENESIS; HUMAN; KARYOTYPE; LATERAL BRAIN VENTRICLE; MELANOCYTIC NEVUS; NERVE CELL DIFFERENTIATION; NONHUMAN; NOONAN SYNDROME; OPTIC CHIASM; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PILOCYTIC ASTROCYTOMA; PILOMYXOID ASTROCYTOMA; PLEOMORPHIC XANTHOASTROCYTOMA; POINT MUTATION; POLYMERASE CHAIN REACTION; POSTERIOR FOSSA; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROMYELOCYTIC LEUKEMIA; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; REVIEW; SUBEPENDYMAL GIANT CELL ASTROCYTOMA; TELOMERE HOMEOSTASIS; TUBEROUS SCLEROSIS; ANIMAL; BRAIN TUMOR; CANCER GRADING; GENETICS; METABOLISM; PATHOLOGY;

ANIMALS; ASTROCYTOMA; BRAIN NEOPLASMS; HUMANS; NEOPLASM GRADING;

MLCS; MLOWN;

EID: 84875893063     PISSN: 15534006     EISSN: 15534014     Source Type: Book Series    
DOI: 10.1146/annurev-pathol-020712-164009     Document Type: Review

References (106)

1. Sievert AJ, Fisher MJ. 2009. Pediatric low-grade gliomas. J. Child Neurol. 24:1397-4088
2. Fisher PG, Tihan T, Goldthwaite PT, Wharam MD, Carson BS, et al. 2008. Outcome analysis of childhood low-grade astrocytomas. Pediatr. Blood Cancer 51:245-500
3. Pollack IF, Claassen D, Al-Shboul Q, Janosky JE, Deutsch M. 1995. Low-grade gliomas of the cerebral hemispheres in children: an analysis of 71 cases. J. Neurosurg. 82:536-477
4. Pencalet P, Maixner W, Sainte-Rose C, Lellouch-Tubiana A, Cinalli G, et al. 1999. Benign cerebellar astrocytomas in children. J. Neurosurg. 90:265-733
5. Fernandez C, Figarella-Branger D, Girard N, Bouvier-Labit C, Gouvernet J, et al. 2003. Pilocytic astrocytomas in children: prognostic factors - a retrospective study of 80 cases. Neurosurgery 53:544-555
6. Stuer C, Vilz B, MajoresM, Becker A, Schramm J, SimonM. 2007. Frequent recurrence and progression in pilocytic astrocytoma in adults. Cancer 110:2799-8088
7. Takei H, Yogeswaren ST, Wong KK, Mehta V, Chintagumpala M, et al. 2008. Expression of oligodendroglial differentiation markers in pilocytic astrocytomas identifies two clinical subsets and shows a significant correlation with proliferation index and progression free survival. J. Neurooncol. 86:183-900
8. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. 2007. WHO Classification of Tumours of the Central Nervous System. Lyon, Fr.: IARCC
9. Dirven CM, Koudstaal J, Mooij JJ, Molenaar WM. 1998. The proliferative potential of the pilocytic astrocytoma: the relation between MIB-1 labeling and clinical and neuro-radiological follow-up. J. Neurooncol. 37:9-166
10. Bowers DC, Gargan L, Kapur P, Reisch JS, Mulne AF, et al. 2003. Study of the MIB-1 labeling index as a predictor of tumor progression in pilocytic astrocytomas in children and adolescents. J. Clin. Oncol. 21:2968-733
11. Tibbetts KM, Emnett RJ, Gao F, Perry A, GutmannDH, Leonard Jr. 2009. Histopathologic predictors of pilocytic astrocytoma event-free survival. Acta Neuropathol. 117:657-655
12. Fisher BJ, Naumova E, Leighton CC, Naumov GN, Kerklviet N, et al. 2002. Ki-67: a prognostic factor for low-grade glioma? Int. J. Radiat. Oncol. Biol. Phys. 52:996-10011
13. Horbinski C, NikiforovaMN, Hagenkord JM, Hamilton RL, Pollack IF. 2012. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol. 14:777-899
14. Rodriguez FJ, Scheithauer BW, Burger PC, Jenkins S, Giannini C. 2010. Anaplasia in pilocytic astrocytoma predicts aggressive behavior. Am. J. Surg. Pathol. 34:147-600
15. Tihan T, Fisher PG, Kepner JL, Godfraind C, McComb RD, et al. 1999. Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J. Neuropathol. Exp. Neurol. 58:1061- 688
16. Johnson MW, Eberhart CG, Perry A, Tihan T, Cohen KJ, et al. 2010. Spectrum of pilomyxoid astrocytomas: intermediate pilomyxoid tumors. Am. J. Surg. Pathol. 34:1783-911
17. Reifenberger G, Kaulich K, Wiestler OD, Blumcke I. 2003. Expression of the CD34 antigen in pleomorphic xanthoastrocytomas. Acta Neuropathol. 105:358-644
18. Buccoliero AM, Franchi A, Castiglione F, Gheri CF, Mussa F, et al. 2009. Subependymal giant cell astrocytoma (SEGA): Is it an astrocytoma? Morphological, immunohistochemical and ultrastructural study. Neuropathology 29:25-300
19. Jozwiak J, Jozwiak S, Skopinski P. 2005. Immunohistochemical and microscopic studies on giant cells in tuberous sclerosis. Histol. Histopathol. 20:1321-266
20. Sharma MC, Ralte AM, Gaekwad S, Santosh V, Shankar SK, Sarkar C. 2004. Subependymal giant cell astrocytoma - a clinicopathological study of 23 cases with special emphasis on histogenesis. Pathol. Oncol. Res. 10:219-244
21. Cheng Y, Pang JC, Ng HK, Ding M, Zhang SF, et al. 2000. Pilocytic astrocytomas do not show most of the genetic changes commonly seen in diffuse astrocytomas. Histopathology 37:437-444
22. Buccoliero AM, Castiglione F, Rossi Degl'innocenti D, Gheri CF, Genitori L, Taddei GL. 2012. IDH1 mutation in pediatric gliomas: Has it a diagnostic and prognostic value? Fetal Pediatr. Pathol. 31:278-822
23. Pollack IF, Hamilton RL, Sobol RW, NikiforovaMN, Lyons-WeilerMA, et al. 2011. IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. Child's Nerv. Syst. 27:87-944
24. Paugh BS,QuC, Jones C, Liu Z, Adamowicz-Brice M, et al. 2010. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J. Clin. Oncol. 28:3061-688
25. Pfister S, Janzarik WG, Remke M, Ernst A,Werft W, et al. 2008. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J. Clin. Investig. 118:1739-499
26. Deshmukh H, Yeh TH, Yu J, Sharma MK, Perry A, et al. 2008. High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. Oncogene 27:4745-511
27. Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG. 2008. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J. Neuropathol. Exp. Neurol. 67:878-877
28. Sievert AJ, Jackson EM, Gai X, Hakonarson H, Judkins AR, et al. 2009. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol. 19:449-588
29. JonesDT, Kocialkowski S,Liu L, PearsonDM,BacklundLM,et al. 2008. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 68:8673- 777
30. Forshew T, Tatevossian RG, Lawson AR, Ma J, Neale G, et al. 2009. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J. Pathol. 218:172-811
31. Jacob K, Albrecht S, Sollier C, Faury D, Sader E, et al. 2009. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br. J. Cancer 101:722-333
32. Yu J, Deshmukh H, Gutmann RJ, Emnett RJ, Rodriguez FJ, et al. 2009. Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology 73:1526-311
33. Korshunov A, Meyer J, Capper D, Christians A, Remke M, et al. 2009. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol. 118:401- 55
34. Lawson AR, Tatevossian RG, Phipps KP, Picker SR, Michalski A, et al. 2010. RAF gene fusions are specific to pilocytic astrocytoma in a broad paediatric brain tumour cohort. Acta Neuropathol. 120:271- 733
35. HorbinskiC,Hamilton RL,Nikiforov Y, Pollack IF. 2010. Association ofmolecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol. 119:641-499
36. Tihan T, Ersen A, Qaddoumi I, Sughayer MA, Tolunay S, et al. 2012. Pathologic characteristics of pediatric intracranial pilocytic astrocytomas and their impact on outcome in 3 countries: amulti-institutional study. Am. J. Surg. Pathol. 36:43-555
37. Cin H, Meyer C, Herr R, Janzarik WG, Lambert S, et al. 2011. Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism ofMAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol. 121:763-744
38. Tian Y, Rich BE, Vena N, Craig JM, Macconaill LE, et al. 2011. Detection of KIAA1549-BRAF fusion transcripts in formalin-fixed paraffin-embedded pediatric low-grade gliomas. J. Mol. Diagn. 13:669-777
39. Lin A, Rodriguez FJ, Karajannis MA, Williams SC, Legault G, et al. 2012. 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. 71:66-722
40. Lawson AR, Hindley GF, Forshew T, Tatevossian RG, Jamie GA, et al. 2011. RAF gene fusion breakpoints in pediatric brain tumors are characterized by significant enrichment of sequencemicrohomology. Genome Res. 21:505-144
41. Fryssira H, Leventopoulos G, Psoni S, Kitsiou-Tzeli S, Stavrianeas N, Kanavakis E. 2008. Tumor development in three patients with Noonan syndrome. Eur. J. Pediatr. 167:1025-311
42. Sanford RA, Bowman R, Tomita T, De Leon G, Palka P. 1999. A 16-year-old male with Noonan's syndrome develops progressive scoliosis and deteriorating gait. Pediatr. Neurosurg. 30:47-522
43. Schuettpelz LG, McDonald S, Whitesell K, Desruisseau DM, Grange DK, et al. 2009. Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr. Blood Cancer 53:1147-499
44. Karafin M, Jallo GI, Ayars M, Eberhart CG, Rodriguez FJ. 2011. Rosette forming glioneuronal tumor in association with Noonan syndrome: pathobiological implications. Clin. Neuropathol. 30:297-3000
45. Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP. 2009. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28:2119-233
46. Schindler G, Capper D,Meyer J, Janzarik W, Omran H, et al. 2011. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 121:397-4055
47. Eisenhardt AE, Olbrich H, Roring M, Janzarik W, Anh TN, et al. 2010. Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma. Int. J. Cancer 129:2297-3033
48. Sharma MK, Zehnbauer BA, Watson MA, Gutmann DH. 2005. RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma. Neurology 65:1335-366
49. Janzarik WG, Kratz CP, Loges NT, Olbrich H, Klein C, et al. 2007. Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. Neuropediatrics 38:61-633
50. Emuss V, Garnett M, Mason C,Marais R. 2005. Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. Cancer Res. 65:9719-266
51. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, et al. 2002. Mutations of the BRAF gene in human cancer. Nature 417:949-544
52. Rodriguez EF, Scheithauer BW, Giannini C, Rynearson A, Cen L, et al. 2011. PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma. Acta Neuropathol. 121:407-200
53. Hawkins C, Walker E, Mohamed N, Zhang C, Jacob K, et al. 2011. BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin. Cancer Res. 17:4790-988
54. Schiffman JD, Hodgson JG, VandenBerg SR, Flaherty P, Polley MY, et al. 2010. Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res. 70:512-199
55. HasselblattM, Riesmeier B, Lechtape B, Brentrup A, StummerW, et al. 2011. BRAF-KIAA1549 fusion transcripts are less frequent in pilocytic astrocytomas diagnosed in adults. Neuropathol. Appl. Neurobiol. 37:803-66
56. Sakai K, Miyahara T, Tsutsumi K, Kaneko T, Fukushima M, et al. 2011. Spontaneous regression of multicentric pilocytic astrocytoma with CSF dissemination in an adult. Brain Tumor Pathol. 28:151-566
57. Gunny RS, Hayward RD, Phipps KP, Harding BN, Saunders DE. 2005. Spontaneous regression of residual low-grade cerebellar pilocytic astrocytomas in children. Pediatr. Radiol. 35:1086-911
58. Michaloglou C, Vredeveld LC, SoengasMS, Denoyelle C, Kuilman T, et al. 2005. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720-244
59. McDuff FK, Turner SD. 2011. Jailbreak: oncogene-induced senescence and its evasion. Cell Signal. 23:6-133
60. Larsson LG. 2011. Oncogene- and tumor suppressor gene-mediated suppression of cellular senescence. Semin. Cancer Biol. 21:367-766
61. Raabe EH, Lim KS, Kim JM, Meeker A, Mao XG, et al. 2011. BRAF activation induces transformation and then senescence in human neural stem cells: a pilocytic astrocytoma model. Clin. Cancer Res. 17:3590- 999
62. Jacob K, Quang-Khuong DA, Jones DT, Witt H, Lambert S, et al. 2011. Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin. Cancer Res. 17:4650-600
63. Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, et al. 2006. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10:459-722
64. Chong EY, Lam PY, Poon WS, Ng HK. 1998. Telomerase expression in gliomas including the nonastrocytic tumors. Hum. Pathol. 29:599-6033
65. Tabori U, Vukovic B, ZielenskaM, Hawkins C, Braude I, et al. 2006. The role of telomere maintenance in the spontaneous growth arrest of pediatric low-grade gliomas. Neoplasia 8:136-422
66. Tabori U, Dome JS. 2007. Telomere biology of pediatric cancer. Cancer Investig. 25:197-2088
67. Heaphy CM, Subhawong AP, Hong SM, Goggins MG,Montgomery EA, et al. 2011. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am. J. Pathol. 179:1608-155
68. Slatter T,Gifford-Garner J,Wiles A, Tan X, Chen YJ, et al. 2010. Pilocytic astrocytomas have telomereassociated promyelocytic leukemia bodies without alternatively lengthened telomeres. Am. J. Pathol. 177:2694-7000
69. Listernick R, Charrow J, Greenwald MJ, Esterly NB. 1989. Optic gliomas in children with neurofibromatosis type 1. J. Pediatr. 114:788-922
70. Rodriguez FJ, Giannini C, Asmann YW, SharmaMK, Perry A, et al. 2008. Gene expression profiling of NF-1-associated and sporadic pilocytic astrocytoma identifies aldehyde dehydrogenase 1 family member L1 (ALDH1L1) as an underexpressed candidate biomarker in aggressive subtypes. J. Neuropathol. Exp. Neurol. 67:1194-2044
71. Kluwe L, Hagel C, Tatagiba M, Thomas S, Stavrou D, et al. 2001. Loss of NF1 alleles distinguish sporadic from NF1-associated pilocytic astrocytomas. J. Neuropathol. Exp. Neurol. 60:917-200
72. Wimmer K, Eckart M, Meyer-Puttlitz B, Fonatsch C, Pietsch T. 2002. Mutational and expression analysis of the NF1 gene argues against a role as tumor suppressor in sporadic pilocytic astrocytomas. J. Neuropathol. Exp. Neurol. 61:896-9022
73. SharmaMK, Mansur DB, Reifenberger G, Perry A, Leonard JR, et al. 2007. Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin. Cancer Res. 67:890-9000
74. Banerjee S, Gianino SM, Gao F, Christians U, Gutmann DH. 2011. Interpreting mammalian target of rapamycin and cell growth inhibition in a genetically engineered mousemodel of Nf1-deficient astrocytes. Mol. Cancer Ther. 10:279-911
75. Warrington NM, Woerner BM, Daginakatte GC, Dasgupta B, Perry A, et al. 2007. Spatiotemporal differences in CXCL12 expression and cyclic AMP underlie the unique pattern of optic glioma growth in neurofibromatosis type 1. Cancer Res. 67:8588-955
76. Babcock JT, Quilliam LA. 2011. Rheb/mTOR activation and regulation in cancer: novel treatment strategies beyond rapamycin. Curr. Drug Targets 12:1223-311
77. Mendoza MC, Er EE, Blenis J. 2011. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem. Sci. 36:320-288
78. Magnuson B, Ekim B, Fingar DC. 2012. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem. J. 441:1-211
79. Chan JA, Zhang H, Roberts PS, Jozwiak S, Wieslawa G, et al. 2004. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: Biallelic inactivation ofTSC1 orTSC2 leads tomTORactivation. J. Neuropathol. Exp. Neurol. 63:1236-422
80. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, et al. 2010. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N. Engl. J. Med. 363:1801-111
81. Dasgupta B, Yi Y, Chen DY, Weber JD, GutmannDH. 2005. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. 65:2755-600
82. Lee DY, YehTH, Emnett RJ,White CR,Gutmann DH. 2010. Neurofibromatosis 1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes Dev. 24:2317- 299
83. Jentoft M, Giannini C, Cen L, Scheithauer BW, Hoesley B, et al. 2010. Phenotypic variations in NF1- associated low grade astrocytomas: possible role for increased mTOR activation in a subset. Int. J. Clin. Exp. Pathol. 4:43-577
84. Ellezam B, Theeler BJ, Luthra R, Adesina AM, Aldape KD, Gilbert MR. 2012. Recurrent PIK3CA mutations in rosette-forming glioneuronal tumor. Acta Neuropathol. 123:285-877
85. Rickman DS, Bobek MP, Misek DE, Kuick R, Blaivas M, et al. 2001. Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Res. 61:6885-911
86. Colin C, BaezaN,Bartoli C, Fina F, EudesN, et al. 2006. Identification of genes differentially expressed in glioblastoma versus pilocytic astrocytoma using suppression subtractive hybridization. Oncogene 25:2818- 266
87. Hunter S, Young A,Olson J, Brat DJ, Bowers G, et al. 2002. Differential expression between pilocytic and anaplastic astrocytomas: identification of apolipoprotein D as a marker for low-grade, non-infiltrating primary CNS neoplasms. J. Neuropathol. Exp. Neurol. 61:275-811
88. Rorive S, Maris C, Debeir O, Sandras F, Vidaud M, et al. 2006. Exploring the distinctive biological characteristics of pilocytic and low-grade diffuse astrocytomas using microarray gene expression profiles. J. Neuropathol. Exp. Neurol. 65:794-8077
89. Gutmann DH, Hedrick NM, Li J, Nagarajan R, Perry A, Watson MA. 2002. Comparative gene expression profile analysis of neurofibromatosis 1-associated and sporadic pilocytic astrocytomas. Cancer Res. 62:2085-911
90. Wong KK, Chang YM, Tsang YT, Perlaky L, Su J, et al. 2005. Expression analysis of juvenile pilocytic astrocytomas by oligonucleotide microarray reveals two potential subgroups. Cancer Res. 65:76-844
91. SharmaMK, WatsonMA,Lyman M, Perry A, Aldape KD, et al. 2006. Matrilin-2 expression distinguishes clinically relevant subsets of pilocytic astrocytoma. Neurology 66:127-300
92. Tchoghandjian A, Fernandez C, Colin C, El Ayachi I, Voutsinos-Porche B, et al. 2009. Pilocytic astrocytoma of the optic pathway: a tumour deriving from radial glia cells with a specific gene signature. Brain 132:1523-355
93. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, et al. 2012. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 123:465-722
94. Dougherty MJ, Santi M, Brose MS, Ma C, Resnick AC, et al. 2010. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro-Oncology 12:621-300
95. Dias-Santagata D, Lam Q, Vernovsky K, Vena N, Lennerz JK, et al. 2011. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS ONE 6:e179488
96. Sharma SG, Gulley ML. 2010. BRAF mutation testing in colorectal cancer. Arch Pathol. Lab. Med. 134:1225-288
97. Capper D, PreusserM, Habel A, Sahm F, Ackermann U, et al. 2011. Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol. 122:11-199
98. Setty P, Gessi M, Waha A, Hammes J, El-Maarri O, Pietsch T. 2011. Sensitive determination of BRAF copy number in clinical samples by pyrosequencing. Diagn. Mol. Pathol. 20:148-577
99. Hegedus B, Banerjee D, Yeh TH, Rothermich S, Perry A, et al. 2008. Preclinical cancer therapy in a mouse model of neurofibromatosis 1 optic glioma. Cancer Res. 68:1520-288
100. Bajenaru ML, Garbow JR, Perry A, Hernandez MR, Gutmann DH. 2005. Natural history of neurofibromatosis 1-associated optic nerve glioma in mice. Ann. Neurol. 57:119-277
101. Gronych J, Korshunov A, Bageritz J, Milde T, Jugold M, et al. 2011. An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice. J. Clin. Investig. 121:1344-488
102. Bax DA, Little SE, Gaspar N, Perryman L, Marshall L, et al. 2009. Molecular and phenotypic characterisation of paediatric glioma cell lines as models for preclinical drug development. PLoS ONE 4:e52099
103. Shahabi V, Whitney G, Hamid O, Schmidt H, Chasalow S, et al. 2012. Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol. Immunother. 61:733-377
104. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, et al. 2011. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364:2507-166
105. Franz DN, Leonard J, Tudor C, Chuck G, Care M, et al. 2006. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann. Neurol. 59:490-988
106. Packer RJ, YalonM, Rood BR, ChaoM,Miller MM, et al. 2010. Phase I/II study of Tarceva/rapamycin for recurrent pediatric low-grade gliomas (LGG). Neuro-Oncology 12:ii200