In conclusion, activation of the MAPK pathway under- pins the development of PA and occurs most frequently via the formation of fusion genes involving the RAF kinases. The fusion genes are highly specific to PA when compared to other types of brain cancer, which affords a diagnostic opportunity for the improved clas- sification of PA in clinical samples. This is particularly important given the varied morphology that PAs can exhibit and the less aggressive treatment course that is followed for PA in comparison to higher grade brain tumors, which usually necessitate adjuvant treatment to try to control the disease. In addition to the potential diagnostic utility of RAF fusion genes in PA, new ther- apeutic options are also indicated. In the short term, drugs already designed to target BRAF or downstream targets (such as MEK) are now entering preclinical and early clinical trials for PA. In the longer term, novel targeted agents against MAPK pathway mem- bers and/or the BRAF fusion itself should be beneficial for a substantial number of patients with PA.
References
Agamanolis DP, Malone JM (1995) Chromosomal abnormali- ties in 47 pediatric brain tumors. Cancer Genet Cytogenet 81:125–134
Armstrong GT, Conklin HM, Huang S, Srivastava D, Sanford R, Ellison DW, Merchant TE, Hudson MM, Hoehn ME, Robison LL, Gajjar A, Morris EB (2011) Survival and long- term health and cognitive outcomes after low-grade glioma.
Neuro Oncol 13:223–234
Bigner SH, McLendon RE, Fuchs H, McKeever PE, Friedman HS (1997) Chromosomal characteristics of childhood brain tumors. Cancer Genet Cytogenet 97:125–134
Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, Zhang KY, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D’Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596–599 CBTRUS (2011) CBTRUS statistical report: primary brain and
central nervous system tumors diagnosed in the United States in 2004–2007. Source: Central Brain Tumor Registry of the United States, Hinsdale, IL. website:www.cbtrus.org Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova
MN, Rabes HM, Fagin JA, Nikiforov YE (2005) Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK path- way activation in thyroid cancer. J Clin Invest 115:94–101 Cin H, Meyer C, Herr R, Janzarik WG, Lambert SR, Jones DT,
Jacob K, Benner A, Witt H, Remke M, Bender S, Falkenstein F, Van Anh TN, Olbrich H, von Deimling A, Pekrun A, Kulozik AE, Gnekow A, Scheurlen W, Witt O, Omran H, Jabado N, Collins VP, Brummer T, Marschalek R, Lichter P, Korshunov A, Pfister SM (2011) Oncogenic FAM131B- BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilo- cytic astroctyoma. Acta Neuropathol 121:763–774 Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S,
Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard- Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954
Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279–3290 Dirven CM, Mooij JJ, Molenaar WM (1997) Cerebellar pilocytic
astrocytoma: a treatment protocol based upon analysis of 73 cases and a review of the literature. Childs Nerv Syst 13:
17–23
Eisenhardt AE, Olbrich H, Roring M, Janzarik W, Van Anh TN, Cin H, Remke M, Witt H, Korshunov A, Pfister SM, Omran H, Brummer T (2010) Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma. Int J Cancer
Endris V, Wogatzky B, Leimer U, Bartsch D, Zatyka M, Latif F, Maher ER, Tariverdian G, Kirsch S, Karch D, Rappold GA (2002) The novel Rho-GTPase activating gene MEGAP/
srGAP3 has a putative role in severe mental retardation. Proc Natl Acad Sci USA 99:11754–11759
Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819
Forshew T, Tatevossian RG, Lawson AR, Ma J, Neale G, Ogunkolade BW, Jones TA, Aarum J, Dalton J, Bailey S, Chaplin T, Carter RL, Gajjar A, Broniscer A, Young BD, Ellison DW, Sheer D (2009) Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilo- cytic astrocytomas. J Pathol 218:172–181
Gronych J, Korshunov A, Bageritz A, Milde T, Jugold M, Hambardzumyan D, Remke M, Hartmann C, Witt H, Jones DT, Witt O, Heiland S, Bendszus M, Holland EC, Pfister S, Lichter P (2011) Mutated BRAF kinase domain alone is suf- ficient to induce pilocytic astrocytoma in mice. J Clin Invest 121:1344–1348
Jacob K, Albrecht S, Sollier C, Faury D, Sader E, Montpetit A, Serre D, Hauser P, Garami M, Bognar L, Hanzely Z, Montes JL, Atkinson J, Farmer JP, Bouffet E, Hawkins C, Tabori U, Jabado N (2009) Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer 101:722–733
Jacob K, Quang-Khuong DA, Jones DT, Witt H, Lambert SR, Albrecht S, Witt O, Vezina C, Shirinian M, Faury D, Garami M, Hauser P, Klekner A, Bognar L, Farmer JP, Montes JL, Atkinson J, Hawkins C, Korshunov A, Collins VP, Pfister SM, Tabori U, Jabado N (2011) Genetic aberrations lead- ing to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 17:4650–4660
Jones DT, Ichimura K, Liu L, Pearson DM, Plant K, Collins VP (2006) Genomic analysis of pilocytic astrocytomas at 0.97 Mb resolution shows an increasing tendency toward chromosomal copy number change with age. J Neuropathol Exp Neurol 65:1049–1058
Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP (2008) Tandem duplication produc- ing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673–8677 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 astrocy- toma. Oncogene 28:2119–2123
Kolch W (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6:827–837 Lawson AR, Tatevossian RG, Phipps KP, Picker SR, Michalski
A, Sheer D, Jacques TS, Forshew T (2010) RAF gene fusions are specific to pilocytic astrocytoma in a broad paediatric brain tumour cohort. Acta Neuropathol 120:271–273 Lawson AR, Hindley GF, Forshew T, Tatevossian RG, Jamie
GA, Kelly GP, Neale GA, Ma J, Jones TA, Ellison DW, Sheer D (2011) RAF gene fusion breakpoints in pediatric brain tumors are characterized by significant enrichment of sequence microhomology. Genome Res 21:505–514 Listernick R, Charrow J, Gutmann DH (1999) Intracranial
gliomas in neurofibromatosis type 1. Am J Med Genet 89:38–44
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system.
Acta Neuropathol 114:97–109
Mischel PS, Cloughesy TF (2003) Targeted molecular therapy of GBM. Brain Pathol 13:52–61
Ohgaki H, Kleihues P (2005) Epidemiology and etiology of gliomas. Acta Neuropathol 109:93–108
Palanisamy N, Ateeq B, Kalyana-Sundaram S, Pflueger D, Ramnarayanan K, Shankar S, Han B, Cao Q, Cao X, Suleman K, Kumar-Sinha C, Dhanasekaran SM, Chen YB, Esgueva R, Banerjee S, LaFargue CJ, Siddiqui J, Demichelis F, Moeller P, Bismar TA, Kuefer R, Fullen DR, Johnson TM, Greenson JK, Giordano TJ, Tan P, Tomlins SA, Varambally S, Rubin MA, Maher CA, Chinnaiyan AM (2010) Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 16:793–798
Raabe EH, Lim KS, Kim JM, Meeker A, Mao XG, Nikkhah G, Maciaczyk J, Kahlert U, Jain D, Bar E, Cohen KJ, Eberhart CG (2011) BRAF activation induces transformation and then senescence in human neural stem cells: a pilocytic astrocytoma model. Clin Cancer Res 17:3590–3599 Schiffman JD, Hodgson JG, VandenBerg SR, Flaherty P, Polley
MY, Yu M, Fisher PG, Rowitch DH, Ford JM, Berger MS, Ji H, Gutmann DH, James CD (2010) Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res 70:
512–519
Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold- Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M, Louis DN, Korshunov A, Pfister S, Hartmann C, Paulus W, Reifenberger G, von Deimling A (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xan- thoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121:397–405
Schrock E, Blume C, Meffert MC, du Manoir S, Bersch W, Kiessling M, Lozanowa T, Thiel G, Witkowski R, Ried T,
Cremer T (1996) Recurrent gain of chromosome arm 7q in low-grade astrocytic tumors studied by comparative genomic hybridization. Genes Chromosomes Cancer 15:
199–205
Shen MH, Harper PS, Upadhyaya M (1996) Molecular genetics of neurofibromatosis type 1 (NF1. J Med Genet 33:2–17 Sievert AJ, Jackson EM, Gai X, Hakonarson H, Judkins AR,
Resnick AC, Sutton LN, Storm PB, Shaikh TH, Biegel JA (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 19:449–458
Tihan T, Fisher PG, Kepner JL, Godfraind C, McComb RD, Goldthwaite PT, Burger PC (1999) Pediatric astrocytomas with monomorphous pilomyxoid features and a less favor- able outcome. J Neuropathol Exp Neurol 58:1061–1068 Tomlinson FH, Scheithauer BW, Hayostek CJ, Parisi JE, Meyer
FB, Shaw EG, Weiland TL, Katzmann JA, Jack CR Jr. (1994) The significance of atypia and histologic malignancy in pilo- cytic astrocytoma of the cerebellum: a clinicopathologic and flow cytometric study. J Child Neurol 9:301–310
von Deimling A, Krone W, Menon AG (1995) Neurofibromatosis type 1: pathology, clinical features and molecular genetics. Brain Pathol 5:153–162
Walker C, Joyce KA, Thompson-Hehir J, Davies MP, Gibbs FE, Halliwell N, Lloyd BH, Machell Y, Roebuck MM, Salisbury J, Sibson DR, Du Plessis D, Broome J, Rossi ML (2001) Characterisation of molecular alterations in microdissected archival gliomas. Acta Neuropathol 101:321–333
White FV, Anthony DC, Yunis EJ, Tarbell NJ, Scott RM, Schofield DE (1995) Nonrandom chromosomal gains in pilocytic astrocytomas of childhood. Hum Pathol 26:
979–986