Profil ekspresji genów w gwiaździakach włosowatokomórkowych wieku dziecięcego w odniesieniu do lokalizacji, obrazu radiologiczno‑morfologicznego i przebiegu klinicznego choroby

• Authors: Magdalena Zakrzewska

Title variants

EN

Gene expression profiles of pilocytic astrocytoma in relation to the location, radiological features and clinical course of the disease

• Languages of publication: PL

Abstracts

EN

Pilocytic astrocytoma (PA) is the most common type of brain tumour in paediatric population connected with favourable prognosis although in numbered cases recurrence or dissemination could be observed. PA accounts for 30% of all brain tumours occurring in children. The tumours affect various anatomical structures and show different radiological appearance. Genetics of this tumour as well as the plausible correlations between molecular profile and clinical course of the disease and/or radiological features are still undefined. The purpose of our research was the identification of gene expression profiles related to localization and radiological features of pilocytic astrocytomas and clinical course of the disease. Eighty six children with PAs, operated on in the Department of Neurosurgery, Polish Mother’s Memorial Hospital Research Institute, were included in this study. The group was comprised of 55 males and 31 females. The mean age of patients at the time of diagnosis was 7 years (ranging from 1 to 17 years). All specimens were diagnosed at the Department of Molecular Pathology and Neuropathology Medical University of Lodz, according to the WHO criteria. The analysis was done by high density oligonucleotide microarrays (GeneChip Human Genome U133 Plus 2.0) in 50 snap‑frozen tissue samples diversified in terms of localization (28 cerebellar tumours, 11 optic tracts and hypothalamic tumours, 9 hemispheric tumours, 2 brain stem tumours), radiological appearance (27 solid or mainly solid tumours, 10 cystic tumours where the mural nodule and the cyst wall were enhanced, 8 cystic tumours where only the mural nodule was enhanced, 5 largely necrotic tumours) and clinical course (5 cases of progressive disease after subtotal resection, 2 cases connected with neurofibromatosis type 1). Bioinformatic analyses with using Bioconductor packages were done after normalization of data with using GC‑RMA algorithm. Gene expression profile of pilocytic astrocytomas highly depends on the tumour localization. This correlation reach statistical significance (p=0.001). Eight hundred sixty‑two probesets differentiated tumours of different localization with high significance of global test. Most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes. Analysis of the genes differentiating between radiological features showed much weaker transcriptome differences, with the borderline significance in the global test of association (p=0.88). No genes showed significant association with the tendency to progression in univariate analysis (p=0.83). The results of microarray analysis were confirmed by QRT‑PCR. In the conclusion we showed that gene expression profile in pilocytic astrocytomas is connected with tumour localization and such relationship suggest different origin of PA arising within various anatomical brain structures. Morphological and radiological features as well as clinical course of disease seem not to be associated with different gene expression pattern.

PL

Gwiaździak włosowatokomórkowy (pilocytic astrocytoma, PA) jest najczęstszym nowotworem mózgu występującym u dzieci, u których stanowi około 30% wszystkich nowotworów ośrodkowego układu nerwowego. Biologia molekularna tego nowotworu, pomimo jego częstego występowania w populacji dziecięcej, nie została dotąd wystarczająco poznana, a ewentualnego związku pomiędzy obecnością zaburzeń molekularnych a parametrami klinicznymi nie zdefiniowano na poziomie pozwalającym wykorzystać wyniki badań genetycznych w sferze działań klinicznych. Celem projektu było ustalenie profili ekspresji genów różnicujących gwiaździaka włosowatokomórkowego wieku dziecięcego w zależności od jego umiejscowienia, obrazu radiologiczno‑morfologicznego oraz przebiegu klinicznego choroby. Do badań zakwalifikowano nowotworowy materiał tkankowy pochodzący od 86 dzieci (55 chłopców, 31 dziewcząt) w wieku od 1 do 17 lat (mediana 7 lat). Wszystkie przypadki zostały zdiagnozowane w Zakładzie Patologii Molekularnej i Neuropatologii Uniwersytetu Medycznego w Łodzi w oparciu o kryteria bieżącej klasyfikacji nowotworów ośrodkowego układu nerwowego według WHO. Badania mające na celu identyfikację istotnych biologicznie odchyleń w ekspresji genów przeprowadzono przy użyciu mikromacierzy wysokiej gęstości Human Genome U133 Plus 2.0 (Affymetrix) w 50 przypadkach gwiaździaków włosowatokomórkowych. Badana grupa była zróżnicowana pod względem lokalizacji (28 nowotworów móżdżku i komory IV, 11 nowotworów dróg wzrokowych i podwzgórza, 9 nowotworów półkul mózgu, 2 nowotwory pnia mózgu), obrazu radiologiczno‑morfologicznego (27 nowotworów litych, 10 nowotworów torbielowatych, w których wzmocnieniu kontrastowemu ulegały ściana torbieli i guzek przyścienny, 8 nowotworów torbielowatych z guzkiem przyściennym, w których wzmocnieniu kontrastowemu ulegał tylko guzek przyścienny, 5 nowotworów z obecnymi cechami martwicy centralnej) i przebiegu klinicznego choroby (5 przypadków z cechami klinicznymi progresji choroby po resekcji subtotalnej, 2 przypadki rozwijające się w przebiegu neurofibromatozy typu 1.). Po normalizacji wyników przy użyciu algorytmu GC‑RMA przeprowadzono analizy bioinformatyczne wykorzystujące przede wszystkim pakiet Bioconductor. Wyselekcjonowano 862 geny różnicujące gwiaździaki włosowatokomórkowe pod względem umiejscowienia anatomicznego i wykazano obecność istotnej zależności statystycznej pomiędzy profilem ekspresji genów w odniesieniu do lokalizacji zmiany (p=0,001). Na podstawie uzyskanych wyników dokonano wyboru genów będących markerami molekularnymi dla nowotworów rozwijających się w poszczególnych lokalizacjach (IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1, SIX1). Nie wykazano możliwości zróżnicowania badanej grupy w zależności od obrazu radiologiczno‑morfologicznego. Geny najlepiej różnicujące badaną grupę cechowały się małą amplitudą zmian i brakiem znamienności statystycznej (p=0,88). Podobnie progresja choroby nie była związana z profilem ekspresji genów (p=0,83). Walidację uzyskanych wyników przeprowadzono w oparciu o QRT‑PCR. Przeprowadzone analizy pozwoliły stwierdzić, że gwiaździakiwłosowatokomórkowe w zależności od lokalizacji anatomicznej posiadają charakterystyczny profil ekspresji genów, sugerujący ich różne pochodzenie. Z kolei obraz radiologiczno‑morfologiczny oraz przebieg kliniczny choroby nie mają związku z całkowitym profilem ekspresji genów.

Keywords

EN

children; dzieci; gene expression profiling; gwiaździak włosowatokomórkowy; location; lokalizacja; obraz radiologiczny; outcome; pilocytic astrocytoma; profil ekspresji genów; przebiegchoroby; radiology

Discipline

• MEDICINE: MEDICINE

• Journal: Aktualności Neurologiczne
• Year: 2011
• Volume: 11
• Issue: 3
• Pages: 135-198

Contributors

author

Magdalena Zakrzewska

• Zakład Patologii Molekularnej i Neuropatologii, Uniwersytet Medyczny w Łodzi,

References

• 1. Pomeroy S.L., Tamayo P., Gaasenbeek M. i wsp.: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 2002; 415: 436‑442.
• 2. Eszlinger M., Wiench M., Jarzab B. i wsp.: Meta‑ and reanalysis of gene expression profiles of hot and cold thyroid nodules and papillary thyroid carcinoma for gene groups. J. Clin. Endocrinol. Metab. 2006; 91: 1934‑1942.
• 3. Stępniak P., Handschuh L., Figlerowicz M.: Mikromacierze DNA – analiza danych. Biotechnologia 2008; 4: 68‑87.
• 4. Turkheimer F.E., Roncaroli F., Hennuy B. i wsp.: Chromosomal patterns of gene expression from microarray data: methodology, validation and clinical relevance in gliomas. BMC Bioinformatics 2006; 7: 526.
• 5. Żmieńko A., Handschuh L., Góralski M., Figlerowicz M.: Zastosowanie mikromacierzy DNA w genomice strukturalnej i funkcjonalnej. Biotechnologia 2008; 4: 39‑53.
• 6. Louis D.N., Ohgaki H., Wiestler O.D., Cavenee W.K. (red.): WHO Classification of Tumours of the Central Nervous System. International Agency for Research on Cancer, Lyon 2007.
• 7. Burger P.C., Scheithauer B.W.: Atlas of Tumor Pathology: Tumors of the Central Nervous System. 3rd series. Armed Forces Institute of Pathology, Bethesda 1994.
• 8. Liberski P.P., Kozubski W., Biernat W., Kordek R. (red.): Neuroonkologia kliniczna. Wydawnictwo Czelej Sp. z o.o., Lublin 2011.
• 9. Otero‑Rodríguez A., Sarabia‑Herrero R., García‑Tejeiro M., Zamora‑Martínez T.: Spontaneous malignant transformation of a supratentorial pilocytic astrocytoma. Neurochirurgia (Austr.) 2010; 21: 245‑252.
• 10. Parsa C.F., Givrad S.: Pilocytic astrocytomas as hamartomas: implications for treatment. Br. J. Ophthalmol. 2008; 92: 3‑6.
• 11. Payton J.E., Schmidt J., Yu J. i wsp.: Genome‑wide polymorphism analysis demonstrates a monoclonal origin of pilocytic astrocytoma. Neuropathol. Appl. Neurobiol. 2011; 37: 321‑325.
• 12. Figarella‑Branger D., Daniel L., André P. i wsp.: The PEN5 epitope identifies an oligodendrocyte precursor cell population and pilocytic astrocytomas. Am. J. Pathol. 1999; 155: 1261‑1269.
• 13. Landry C.F., Verity M.A., Cherman L. i wsp.: Expression of oligodendrocytic mRNAs in glial tumors: changes associated with tumor grade and extent of neoplastic infiltration. Cancer Res. 1997; 57: 4098‑4104.
• 14. Takei H., Yogeswaren S.T., Wong K.K. i wsp.: 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. 2008; 86: 183‑190.
• 15. Tchoghandjian A., Fernandez C., Colin C. i wsp.: Pilocytic astrocytoma of the optic pathway: a tumour deriving from radial glia cells with a specific gene signature. Brain 2009; 132: 1523‑1535.
• 16. Cheng Y.C., Lee C.J., Badge R.M. i wsp.: Sox8 gene expression identifies immature glial cells in developing cerebellum and cerebellar tumours. Brain Res. Mol. Brain Res. 2001; 92: 193‑200.
• 17. Eiraku M., Tohgo A., Ono K. i wsp.: DNER acts as a neuronspecific Notch ligand during Bergmann glial development. Nat. Neurosci. 2005; 8: 873‑880.
• 18. Bellil S., Limaiem F., Mahfoudhi H. i wsp.: Descriptive epidemiology of childhood central nervous system tumours in Tunisia. Experience of a single institution over a 15‑year period (1990‑2004). Pediatr. Neurosurg. 2008; 44: 382‑387.
• 19. Larjavaara S., Mäntylä R., Salminen T. i wsp.: Incidence of gliomas by anatomic location. Neuro Oncol. 2007; 9: 319‑325.
• 20. Schmidt L.S., Schmiegelow K., Lahteenmaki P. i wsp.: Incidence of childhood central nervous system tumors in the Nordic countries. Pediatr. Blood Cancer. 2011; 56: 65‑69.
• 21. Ahn Y., Cho B.K., Kim S.K. i wsp.: Optic pathway glioma: outcome and prognostic factors in a surgical series. Childs Nerv. Syst. 2006; 22: 1136‑1142.
• 22. Burkhard C., Di Patre P.L., Schüler D. i wsp.: A populationbased study of the incidence and survival rates in patients with pilocytic astrocytoma. J. Neurosurg. 2003; 98: 1170‑1174.
• 23. Crabtree K.L., Arnold P.M.: Spinal seeding of a pilocytic astrocytoma in an adult, initially diagnosed 18 years previously. Pediatr. Neurosurg. 2010; 46: 66‑70.
• 24. Czyżyk E., Jóźwiak S., Roszkowski M., Schwartz R.A.: Optic pathway gliomas in children with and without neurofibromatosis 1. J. Child Neurol. 2003; 18: 471‑478.
• 25. Makino K., Nakamura H., Yano S., Kuratsu J.: Populationbased epidemiological study of primary intracranial tumors in childhood. Childs Nerv. Syst. 2010; 26: 1029‑1034.
• 26. Ohgaki H., Kleihues P.: Population‑based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J. Neuropathol. Exp. Neurol. 2005; 64: 479‑489.
• 27. Roonprapunt C., Abbott R.: Surgical treatment of brainstem gliomas in children. Neurosurgery Quarterly 2002; 12: 160‑170.
• 28. Piccirilli M., Lenzi J., Delfinis C. i wsp.: Spontaneous regression of optic pathways gliomas in three patients with neurofibromatosis type I and critical review of the literature. Childs Nerv. Syst. 2006; 22: 1332‑1337.
• 29. Rozen W.M., Joseph S., Lo P.A.: Spontaneous regression of low‑grade gliomas in pediatric patients without neurofibromatosis. Pediatr. Neurosurg. 2008; 44: 324‑328.
• 30. Dunn I.F., Agarwalla P.K., Papanastassiou A.M. i wsp.: Multiple pilocytic astrocytomas of the cerebellum in a 17‑year‑old patient with neurofibromatosis type I. Childs Nerv. Syst. 2007; 23: 1191‑1194.
• 31. Tada K., Kochi M., Saya H. i wsp.: Preliminary observations on genetic alterations in pilocytic astrocytomas associated with neurofibromatosis 1. Neuro Oncol. 2003; 5: 228‑234.
• 32. Schuettpelz L.G., McDonald S., Whitesell K. i wsp.: Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr. Blood Cancer 2009; 53: 1147‑1149.
• 33. Subbiah V., Huff V., Wolff J.E. i wsp.: Bilateral gonadoblastoma with dysgerminoma and pilocytic astrocytoma with WT1 GT‑IVS9 mutation: a 46 XY phenotypic female with Frasier syndrome. Pediatr. Blood Cancer 2009; 53: 1349‑1351.
• 34. Zakrzewski K., Fiks T., Liberski P.P. i wsp.: Nowotwory ośrodkowego układu nerwowego u dzieci i młodzieży. Pediatr. Pol. 2005; 80: 17‑22.
• 35. Bowers D.C., Krause T.P., Aronson L.J. i wsp.: Second surgery for recurrent pilocytic astrocytoma in children. Pediatr. Neurosurg. 2001; 34: 229‑234.
• 36. Fisher P.G., Tihan T., Goldthwaite P.T. i wsp.: Outcome analysis of childhood low‑grade astrocytomas. Pediatr. Blood Cancer 2008; 51: 245‑250.
• 37. Komotar R.J., Burger P.C., Carson B.S. i wsp.: Pilocytic and pilomyxoid hypothalamic/chiasmatic astrocytomas. Neurosurgery 2004; 54: 72‑80.
• 38. Dirks P.B., Jay V., Becker L.E. i wsp.: Development of anaplastic changes in low‑grade astrocytomas of childhood. Neurosurgery 1994; 34: 68‑78.
• 39. Krieger M.D., Gonzalez‑Gomez I., Levy M.L., McComb J.G.: Recurrence patterns and anaplastic change in a longterm study of pilocytic astrocytomas. Pediatr. Neurosurg. 1997; 27: 1‑11.
• 40. Jeon Y.K., Cheon J.E., Kim S.K. i wsp.: Clinicopathological features and global genomic copy number alterations of pilomyxoid astrocytoma in the hypothalamus/optic pathway: comparative analysis with pilocytic astrocytoma using arraybased comparative genomic hybridization. Mod. Pathol. 2008; 21: 1345‑1356.
• 41. Jones D.T., Ichimura K., Liu L. i wsp.: Genomic analysis of pilocytic astrocytomas at 0.97 Mb resolution shows an increasing tendency toward chromosomal copy numberchange with age. J. Neuropathol. Exp. Neurol. 2006; 65: 1049‑1058
• 42. Roberts P., Chumas P.D., Picton S. i wsp.: A review of the cytogenetics of 58 pediatric brain tumors. Cancer Genet. Cytogenet. 2001; 131: 1‑12.
• 43. Sanoudou D., Tingby O., Ferguson‑Smith M.A. i wsp.: Analysis of pilocytic astrocytoma by comparative genomic hybridization. Br. J. Cancer 2000; 82: 1218‑1222.
• 44. Zattara‑Cannoni H., Gambarelli D., Lena G. i wsp.: Are juvenile pilocytic astrocytomas benign tumors? A cytogenetic study in 24 cases. Cancer Genet. Cytogenet. 1998; 104: 157‑160.
• 45. Kimmel D.W., O’Fallon J.R., Scheithauer B.W. i wsp.: Prognostic value of cytogenetic analysis in human cerebral astrocytomas. Ann. Neurol. 1992; 31: 534‑542.
• 46. Orr L.C., Fleitz J., McGavran L. i wsp.: Cytogenetics in pediatric low‑grade astrocytomas. Med. Pediatr. Oncol. 2002; 38: 173‑177.
• 47. Pfister S., Janzarik W.G., Remke M. i wsp.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low‑grade astrocytomas. J. Clin. Invest. 2008; 118: 1739‑1749.
• 48. Sievert A.J., Jackson E.M., Gai X. i wsp.: 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. 2009; 19: 449‑458.
• 49. Bar E.E., Lin A., Tihan T. i wsp.: Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J. Neuropathol. Exp. Neurol. 2008; 67: 878‑887.
• 50. Forshew T., Tatevossian R.G., Lawson A.R i wsp.: Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J. Pathol. 2009; 218: 172‑181.
• 51. Jones D.T., Kocialkowski S., Liu L. i wsp.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008; 68: 8673‑8677.
• 52. Jones D.T., Kocialkowski S., Liu L. i wsp.: 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: 2119‑2123.
• 53. Eisenhardt A.E., Olbrich H., Röring M. i wsp.: Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma. Int. J. Cancer 2011; 129: 2297‑2303.
• 54. Korshunov A., Meyer J., Capper D. i wsp.: Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol. 2009; 118: 401‑405.
• 55. Jacob K., Albrecht S., Sollier C. i wsp.: Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br. J. Cancer 2009; 101: 722‑733.
• 56. Tatevossian R.G., Lawson A.R., Forshew T. i wsp.: MA PK pathway activation and the origins of pediatric low‑grade astrocytomas. J. Cell. Physiol. 2010; 222: 509‑514.
• 57. Janzarik W.G., Kratz C.P., Loges N.T. i wsp.: Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. Neuropediatrics 2007; 38: 61‑63.
• 58. Potter N., Karakoula A., Phipps K.P. i wsp.: Genomic deletions correlate with underexpression of novel candidate genes at six loci in pediatric pilocytic astrocytoma. Neoplasia 2008; 10: 757‑772.
• 59. Sharma M.K., Zehnbauer B.A., Watson M.A., Gutmann D.H.: RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma. Neurology 2005; 65: 1335‑1336.
• 60. Huang H., Hara A., Homma T. i wsp.: Altered expression of immune defense genes in pilocytic astrocytomas. J. Neuropathol. Exp. Neurol. 2005; 64: 891‑901.
• 61. Addo‑Yobo S.O., Straessle J., Anwar A. i wsp.: Paired overexpression of ErbB3 and Sox10 in pilocytic astrocytoma. J. Neuropathol. Exp. Neurol. 2006; 65: 769‑775.
• 62. Zeng N., Liu L., McCabe M.G. i wsp.: Real‑time quantitative polymerase chain reaction (qPCR) analysis with fluorescence resonance energy transfer (FRET) probes reveals differential expression of the four ERBB4 juxtamembrane region variants between medulloblastoma and pilocytic astrocytoma. Neuropathol. Appl. Neurobiol. 2009; 35: 353‑366.
• 63. Puputti M., Tynninen O., Pernilä P. i wsp.: Expression of KIT receptor tyrosine kinase in endothelial cells of juvenile brain tumors. Brain Pathol. 2010; 20: 763‑770.
• 64. Ball D.W., Jin N., Rosen D.M. i wsp.: Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. J. Clin. Endocrinol. Metab. 2007; 92: 4712‑4718.
• 65. Shannon A.M., Telfer B.A., Smith P.D. i wsp.: The mitogenactivated protein/extracellular signal‑regulated kinase kinase 1/2 inhibitor AZD6244 (ARRY‑142886) enhances the radiation responsiveness of lung and colorectal tumor xenografts. Clin. Cancer Res. 2009; 15: 6619‑6629.
• 66. Foreman N.K., Gore L., Wells D. i wsp.: Gefitinib is effective against juvenile pilocytic astrocytoma in vitro. Pediatr. Blood Cancer 2006; 47: 293‑298.
• 67. McLaughlin M.E., Robson C.D., Kieran M.W. i wsp.: Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (STI‑571, Gleevec): a case report and laboratory investigation. J. Pediatr. Hematol. Oncol. 2003; 25: 644‑648.
• 68. Pollack I.F., Jakacki R.I., Blaney S.M. i wsp.: Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. Neuro Oncol. 2007; 9: 145‑160.
• 69. Qaddoumi I., Sultan I., Broniscer A.: Pediatric low‑grade gliomas and the need for new options for therapy: why and how? Cancer Biol. Ther. 2009; 8: 4‑10.
• 70. Kolb E.A., Gorlick R., Houghton P.J. i wsp.: Initial testing (stage 1) of AZD6244 (ARRY‑142886) by the Pediatric Preclinical Testing Program. Pediatr. Blood Cancer 2010; 55: 668‑677.
• 71. Rush S.Z., Abel T.W., Valadez J.G. i wsp.: Activation of the Hedgehog pathway in pilocytic astrocytomas. Neuro Oncol. 2010; 12: 790‑798.
• 72. Pfister S.M., Korshunov A., Kool M. i wsp.: Molecular diagnostics of CNS embryonal tumors. Acta Neuropathol. 2010; 120: 553‑566.
• 73. Xenaki D., Martin I.B., Yoshida L. i wsp.: F3/contactin and TAG1 play antagonistic roles in the regulation of sonic hedgehog‑induced cerebellar granule neuron progenitor proliferation. Development 2011; 138: 519‑529.
• 74. Riobo N.A., Lu K., Emerson C.P. Jr: Hedgehog signal transduction: signal integration and cross talk in development and cancer. Cell Cycle 2006; 5: 1612‑1615.
• 75. Seto M., Ohta M., Asaoka Y. i wsp.: Regulation of the hedgehog signaling by the mitogen‑activated protein kinase cascade in gastric cancer. Mol. Carcinog. 2009; 48: 703‑712.
• 76. Deshmukh H., Yeh T.H., Yu J. i wsp.: High‑resolution, dualplatform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. Oncogene 2008; 27: 4745‑4751.
• 77. Di Stefano V., Blandino G., Sacchi A. i wsp.: HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function. Oncogene 2004; 23: 5185‑5192.
• 78. Cheng Y., Pang J.C., Ng H.K. i wsp.: Pilocytic astrocytomas do not show most of the genetic changes commonly seen in diffuse astrocytomas. Histopathology 2000; 37: 437‑444.
• 79. Broniscer A., Baker S.J., West A.N. i wsp.: Clinical and molecular characteristics of malignant transformation of low‑grade glioma in children. J. Clin. Oncol. 2007; 25: 682‑689.
• 80. Facoetti A., Ranza E., Nano R.: Proliferation and programmed cell death: role of p53 protein in high and low grade astrocytoma. Anticancer Res. 2008; 28: 15‑19.
• 81. Gottfried Y., Voldavsky E., Yodko L. i wsp.: Expression of the pro‑apoptotic protein ARTS in astrocytic tumors: correlation with malignancy grade and survival rate. Cancer 2004; 101: 2614‑2621.
• 82. Horbinski C., Hamilton R.L., Lovell C. i wsp.: Impact of morphology, MIB‑1, p53 and MGMT on outcome in pilocytic astrocytomas. Brain Pathol. 2010; 20: 581‑588.
• 83. Ishii N., Sawamura Y., Tada M. i wsp.: Absence of p53 gene mutations in a tumor panel representative of pilocytic astrocytoma diversity using a p53 functional assay. Int. J. Cancer 1998; 76: 797‑800.
• 84. Nakamizo A., Inamura T., Ikezaki K. i wsp.: Enhanced apoptosis in pilocytic astrocytoma: a comparative study of apoptosis and proliferation in astrocytic tumors. J. Neurooncol. 2002; 57: 105‑114.
• 85. Patt S., Gries H., Giraldo M. i wsp.: p53 gene mutations in human astrocytic brain tumors including pilocytic astrocytomas. Hum. Pathol. 1996; 27: 586‑589.
• 86. Rodriguez F.J., Scheithauer B.W., Burger P.C. i wsp.: Anaplasia in pilocytic astrocytoma predicts aggressive behavior. Am. J. Surg. Pathol. 2010; 34: 147‑160.
• 87. Tibbetts K.M., Emnett R.J., Gao F. i wsp.: Histopathologic predictors of pilocytic astrocytoma event‑free survival. Acta Neuropathol. 2009; 117: 657‑665.
• 88. Duerr E.M., Rollbrocker B., Hayashi Y. i wsp.: PTEN mutations in gliomas and glioneuronal tumors. Oncogene 1998; 16: 2259‑2264.
• 89. El Ayachi I., Baeza N., Fernandez C. i wsp.: KIAA0510, the 3’‑untranslated region of the tenascin‑ R gene, and tenascin‑R are overexpressed in pilocytic astrocytomas. Neuropathol. Appl. Neurobiol. 2010; 36: 399‑410.
• 90. Tatevossian R.G., Tang B., Dalton J. i wsp.: MYB upregulation and genetic aberrations in a subset of pediatric low‑grade gliomas. Acta Neuropathol. 2010; 120: 731‑743.
• 91. Costello J.F., Plass C., Cavenee W.K.: Aberrant methylation of genes in low‑grade astrocytomas. Brain Tumor Pathol. 2000; 17: 49‑56.
• 92. Gonzalez‑Gomez P., Bello M.J., Lomas J. i wsp.: Epigenetic changes in pilocytic astrocytomas and medulloblastomas. Int. J. Mol. Med. 2003; 11: 655‑660.
• 93. Lorente A., Mueller W., Urdangarín E. i wsp.: RASSF1A, BLU, NORE1A, PTEN and MGMT expression and promoter methylation in gliomas and glioma cell lines and evidence of deregulated expression of de novo DNMTs. Brain Pathol. 2009; 19: 279‑292.
• 94. Uhlmann K., Brinckmann A., Toliat M.R i wsp.: Evaluation of a potential epigenetic biomarker by quantitative methyl-single nucleotide polymorphism analysis. Electrophoresis 2002; 23: 4072‑4079.
• 95. Uhlmann K., Rohde K., Zeller C. i wsp.: Distinct methylation profiles of glioma subtypes. Int. J. Cancer 2003; 106: 52‑59.
• 96. Vladimirova V., Mikeska T., Waha A. i wsp.: Aberrant methylation and reduced expression of LHX9 in malignant gliomas of childhood. Neoplasia 2009; 11: 700‑711.
• 97. Rickman D.S., Bobek M.P., Misek D.E. i wsp.: Distinctive molecular profiles of high‑grade and low‑grade gliomas based on oligonucleotide microarray analysis. Cancer Res. 2001; 61: 6885‑6891.
• 98. Wong K.K., Chang Y.M., Tsang Y.T. i wsp.: Expression analysis of juvenile pilocytic astrocytomas by oligonucleotide microarray reveals two potential subgroups. Cancer Res. 2005; 65: 76‑84.
• 99. Sharma M.K., Watson M.A., Lyman M. i wsp.: Matrilin‑2 expression distinguishes clinically relevant subsets of pilocytic astrocytoma. Neurology 2006; 66: 127‑130.
• 100. Sharma M.K., Mansur D.B., Reifenberger G i wsp.: Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin. Cancer Res. 2007; 67: 890‑900.
• 101. Rorive S., Maris C., Debeir O. i wsp.: Exploring the distinctive biological characteristics of pilocytic and low‑grade diffuse astrocytomas using microarray gene expression profiles. J. Neuropathol. Exp. Neurol. 2006; 65: 794‑807.
• 102. Koeller K.K., Rushing E.J.: From the archives of the AFIP: pilocytic astrocytoma: radiologic‑pathologic correlation. Radiographics 2004; 24: 1693‑1708.
• 103. Zakrzewski K.: Neuro‑imaging for diagnosis of brain neoplasms in children. Pol. J. Pathol. 2001; 52: 213‑229.
• 104. Pencalet P., Maixner W., Sainte‑Rose C. i wsp.: Benign cerebellar astrocytomas in children. J. Neurosurg. 1999; 90: 265‑273.
• 105. Zakrzewski K., Fiks T., Polis L., Liberski P.P.: Posterior fossa tumours in children and adolescents. A clinicopathological study of 216 cases. Folia Neuropathol. 2003; 41: 251‑252.
• 106. Fernandez C., Figarella‑Branger D., Girard N. i wsp.: Pilocytic astrocytomas in children: prognostic factors – a retrospective study of 80 cases. Neurosurgery 2003; 53: 544‑553.
• 107. Strong J.A., Hatten H.P. Jr, Brown M.T. i wsp.: Pilocytic astrocytoma: correlation between the initial imaging features and clinical aggressiveness. AJR Am. J. Roentgenol. 1993; 161: 369‑372.
• 108. Villarejo F., de Diego J.M., de la Riva A.G.: Prognosis of cerebellar astrocytomas in children. Childs Nerv. Syst. 2008; 24: 203‑210.
• 109. Beni‑Adani L., Gomori M., Spektor S., Constantini S.: Cyst wall enhancement in pilocytic astrocytoma: neoplastic or reactive phenomena. Pediatr. Neurosurg. 2000; 32: 234‑239.
• 110. Dorward I.G., Luo J., Perry A. i wsp.: Postoperative imaging surveillance in pediatric pilocytic astrocytomas. J. Neurosurg. Pediatr. 2010; 6: 346‑352.
• 111. Listernick R., Ferner R.E., Liu G.T., Gutmann D.H.: Optic pathway gliomas in neurofibromatosis‑1: controversies and recommendations. Ann. Neurol. 2007; 61: 189‑198.
• 112. Megyesi J.F., Kachur E., Lee D.H. i wsp.: Imaging correlates of molecular signatures in oligodendrogliomas. Clin. Cancer Res. 2004; 10: 4303‑4306.
• 113. Jenkinson M.D., du Plessis D.G., Smith T.S. i wsp.: Histological growth patterns and genotype in oligodendroglial tumours: correlation with MRI features. Brain 2006; 129: 1884‑1891.
• 114. Walker C., du Plessis D.G., Fildes D. i wsp.: Correlation of molecular genetics with molecular and morphological imaging in gliomas with an oligodendroglial component. Clin. Cancer Res. 2004; 10: 7182‑7191.
• 115. Mut M., Turba U.C., Botella A.C. i wsp.: Neuroimaging characteristics in subgroup of GBMs with p53 overexpression. J. Neuroimaging 2007; 17: 168‑174.
• 116. Warshawsky I., Shadrach B., Commane M. i wsp.: Correlation of TP53 immunohistochemistry with TP53 mutations on gliomas. Mod. Pathol. 2004; 17 (supl. 1): 320A.
• 117. Levner I., Drabycz S., Roldan G. i wsp.: Predicting MGMT methylation status of glioblastomas from MRI texture. Med. Image Comput. Comput. Assist. Interv. 2009; 12: 522‑530.
• 118. Eoli M., Menghi F., Bruzzone M.G. i wsp.: Methylation of O6‑methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival. Clin. Cancer Res. 2007; 13: 2606‑2613.
• 119. Maris C., Rorive S., Sandras F. i wsp.: Tenascin‑C expression relates to clinicopathological features in pilocytic and diffuse astrocytomas. Neuropathol. Appl. Neurobiol. 2008; 34: 316‑329.
• 120. Pope W.B., Chen J.H., Dong J. i wsp.: Relationship between gene expression and enhancement in glioblastoma multiforme: exploratory DNA microarray analysis. Radiology 2008; 249: 268‑277.
• 121. Barajas R.F. Jr, Hodgson J.G., Chang J.S. i wsp.: Glioblastoma multiforme regional genetic and cellular expression patterns: influence on anatomic and physiologic MR imaging. Radiology 2010; 254: 564‑576.
• 122. Smoots D.W., Geyer J.R., Lieberman D.M., Berger M.S.: Predicting disease progression in childhood cerebellar astrocytoma. Childs Nerv. Syst. 1998; 14: 636‑648.
• 123. Porto L., Kieslich M., Franz K. i wsp.: Spectroscopy of untreated pilocytic astrocytomas: do children and adults share some metabolic features in addition to their morphologic similarities? Childs Nerv. Syst. 2010; 26: 801‑806.
• 124. Paixão Becker A., de Oliveira R.S., Saggioro F.P. i wsp.: In pursuit of prognostic factors in children with pilocytic astrocytomas. Childs Nerv. Syst. 2010; 26: 19‑28.
• 125. Rosser T., Packer R.J.: Intracranial neoplasms in children with neurofibromatosis 1. J. Child Neurol. 2002; 17: 630‑637; discussion: 646‑651.
• 126. Stüer C., Vilz B., Majores M. i wsp.: Frequent recurrence and progression in pilocytic astrocytoma in adults. Cancer 2007; 110: 2799‑2808.
• 127. Bowers D.C., Gargan L., Kapur P. i wsp.: Study of the MIB-1 labeling index as a predictor of tumor progression in pilocytic astrocytomas in children and adolescents. J. Clin. Oncol. 2003; 21: 2968‑2973.
• 128. Rodriguez F.J., Giannini C., Asmann Y.W. i wsp.: 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. 2008; 67: 1194‑1204.
• 129. MacDonald T.J., Pollack I.F., Okada H. i wsp.: Progressionassociated genes in astrocytoma identified by novel microarray gene expression data reanalysis. Methods Mol. Biol. 2007; 377: 203‑222.
• 130. Marko N.F., Prayson R.A., Barnett G.H., Weil R.J.: Integrated molecular analysis suggests a three‑class model for low‑grade gliomas: a proof‑of‑concept study. Genomics 2010; 95: 16‑24.
• 131. Rodriguez E.F., Scheithauer B.W., Giannini C. i wsp.: PI3K/ AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma. Acta Neuropathol. 2011; 121: 407‑420.
• 132. Tomlinson F.H., Scheithauer B.W., Hayostek C.J. i wsp.: The significance of atypia and histologic malignancy in pilocytic astrocytoma of the cerebellum: a clinicopathologic and flow cytometric study. J. Child Neurol. 1994; 9: 301‑310.
• 133. 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: 641‑649.
• 134. Chomczynski P., Sacchi N.: Single‑step method of RNA isolation by acid guanidinium thiocyanate‑phenol‑chloroform extraction. Anal. Biochem. 1987; 162: 156‑159.
• 135. Efron B., Tibshirani R.: On testing the significance of sets of genes. The Annals of Applied Statistics 2007; 1: 107‑129.
• 136. Subramanian A., Tamayo P., Mootha V.K. i wsp.: Gene set enrichment analysis: a knowledge‑based approach for interpreting genome‑wide expression profiles. Proc. Natl Acad. Sci. USA 2005; 102: 15545‑15550.
• 137. Pfaffl M.W., Horgan G.W., Dempfle L.: Relative expression software tool (REST) for group‑wise comparison and statistical analysis of relative expression results in real‑time PCR. Nucleic Acids Res. 2002; 30: e36.
• 138. Hussain S.F., Yang D., Suki D. i wsp.: The role of human glioma‑infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol. 2006; 8: 261‑279.
• 139. McEvilly R.J., de Diaz M.O., Schonemann M.D. i wsp.: Transcriptional regulation of cortical neuron migration by POU domain factors. Science 2002; 295: 1528‑1532.
• 140. Adesina A.M., Nguyen Y., Mehta V. i wsp.: FOXG1 dysregulation is a frequent event in medulloblastoma. J. Neurooncol. 2007; 85: 111‑122.
• 141. Seoane J., Le H.V., Shen L. i wsp.: Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 2004; 117: 211‑223.
• 142. Andreiuolo F., Puget S., Peyre M. i wsp.: Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. Neuro Oncol. 2010; 12: 1126‑1134.
• 143. Korshunov A., Neben K., Wrobel G. i wsp.: Gene expression patterns in ependymomas correlate with tumor location, grade, and patient age. Am. J. Pathol. 2003; 163: 1721‑1727.
• 144. Mack S.C., Taylor M.D.: The genetic and epigenetic basis of ependymoma. Childs Nerv. Syst. 2009; 25: 1195‑1201.
• 145. Shibata M., Kurokawa D., Nakao H. i wsp.: MicroRNA‑9 modulates Cajal‑Retzius cell differentiation by suppressing Foxg1 expression in mouse medial pallium. J. Neurosci. 2008; 28: 10415‑10421.
• 146. Cheng L., Wu Q., Guryanova O.A. i wsp.: Elevated invasive potential of glioblastoma stem cells. Biochem. Biophys. Res. Commun. 2011; 406: 643‑648.
• 147. Huang Z., Cheng L., Guryanova O.A. i wsp.: Cancer stem cells in glioblastoma – molecular signaling and therapeutic targeting. Protein Cell 2010; 1: 638‑655.
• 148. Augsten M., Hägglöf C., Olsson E. i wsp.: CXCL14 is an autocrine growth factor for fibroblasts and acts as a multimodal stimulator of prostate tumor growth. Proc. Natl Acad. Sci. USA 2009; 106: 3414‑3419.
• 149. Gabrusiewicz K., Ellert‑Miklaszewska A., Lipko M. i wsp.: Characteristics of the alternative phenotype of microglia/ macrophages and its modulation in experimental gliomas. PLoS One 2011; 6: e23902.
• 150. Mangale V.S., Hirokawa K.E., Satyaki P.R. i wsp.: Lhx2 selector activity specifies cortical identity and suppresses hippocampal organizer fate. Science 2008; 319: 304‑309.
• 151. Ando H., Kobayashi M., Tsubokawa T. i wsp.: Lhx2 mediates the activity of Six3 in zebrafish forebrain growth. Dev. Biol. 2005; 287: 456‑468.
• 152. Ikeda K., Kageyama R., Suzuki Y., Kawakami K.: Six1 is indispensable for production of functional progenitor cells during olfactory epithelial development. Int. J. Dev. Biol. 2010; 54: 1453‑1464.
• 153. Kumar J.P.: The sine oculis homeobox (SIX) family of transcription factors as regulators of development and disease. Cell. Mol. Life Sci. 2009; 66: 565‑583.
• 154. Micalizzi D.S., Christensen K.L., Jedlicka P i wsp.: The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial‑mesenchymal transition and metastasis in mice through increasing TGF‑β signaling. J. Clin. Invest. 2009; 119: 2678‑2690.
• 155. Holland P.W., Booth H.A., Bruford E.A.: Classification and nomenclature of all human homeobox genes. BMC Biol. 2007; 5: 47.
• 156. Peters T., Dildrop R., Ausmeier K., Rüther U.: Organization of mouse Iroquois homeobox genes in two clusters suggests a conserved regulation and function in vertebrate development. Genome Res. 2000; 10: 1453‑1462.
• 157. Weinmann A., Galle P.R., Teufel A.: In silico characterization of an Iroquois family‑related homeodomain protein. Int. J. Mol. Med. 2005; 16: 443‑448.
• 158. Bizzoca A., Virgintino D., Lorusso L. i wsp.: Transgenic mice expressing F3/contactin from the TAG‑1 promoter exhibit developmentally regulated changes in the differentiation of cerebellar neurons. Development 2003; 130: 29‑43.
• 159. Deshmukh H., Yu J., Shaik J. i wsp.: Identification of transcriptional regulatory networks specific to pilocytic astrocytoma. BMC Med. Genomics 2011; 4: 57.
• 160. Singh S.K., Hawkins C., Clarke I.D. i wsp.: Identification of human brain tumour initiating cells. Nature 2004; 432: 396‑401.
• 161. Cahoy J.D., Emery B., Kaushal A. i wsp.: A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 2008; 28: 264‑278.
• 162. Horiguchi S., Takahashi J., Kishi Y. i wsp.: Neural precursor cells derived from human embryonic brain retain regional specificity. J. Neurosci. Res. 2004; 75: 817‑824.
• 163. Otero J.J., Rowitch D., Vandenberg S.: OLIG2 is differentially expressed in pediatric astrocytic and in ependymal neoplasms. J. Neurooncol. 2011; 104: 423‑438.
• 164. Taylor M.D., Poppleton H., Fuller C. i wsp.: Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 2005; 8: 323‑335.
• 165. Hirst D.G., Robson T.: Molecular biology: the key to personalised treatment in radiation oncology? Br. J. Radiol. 2010; 83: 723‑728.
• 166. Barker H.E., Chang J., Cox T.R. i wsp.: LOXL2‑mediated matrix remodeling in metastasis and mammary gland involution. Cancer Res. 2011; 71: 1561‑1572.
• 167. Erler J.T., Bennewith K.L., Nicolau M. i wsp.: Lysyl oxidase is essential for hypoxia‑induced metastasis. Nature 2006; 440: 1222‑1226.
• 168. Erler J.T., Giaccia A.J.: Lysyl oxidase mediates hypoxic control of metastasis. Cancer Res. 2006; 66: 10238‑10241.
• 169. Gutmann D.H., Hedrick N.M., Li J. i wsp.: Comparative gene expression profile analysis of neurofibromatosis 1‑associated and sporadic pilocytic astrocytomas. Cancer Res. 2002; 62: 2085‑2091.
• 170. Szabó E., Korpos E., Batmunkh E. i wsp.: Expression of matrilin‑2 in liver cirrhosis and hepatocellular carcinoma. Pathol. Oncol. Res. 2008; 14: 15‑22.
• 171. Wagener R., Ehlen H.W., Ko Y.P. i wsp.: The matrilins – adaptor proteins in the extracellular matrix. FEBS Lett. 2005; 579: 3323‑3329.
• 172. Anthony T.E., Heintz N.: The folate metabolic enzyme ALDH1L1 is restricted to the midline of the early CNS, suggesting a role in human neural tube defects. J. Comp. Neurol. 2007; 500: 368‑383.
• 173. Krupenko S.A., Oleinik N.V.: 10‑formyltetrahydrofolate dehydrogenase, one of the major folate enzymes, is down-regulated in tumor tissues and possesses suppressor effects on cancer cells. Cell Growth Differ. 2002; 13: 227‑236.
• 174. Deak K.L., Dickerson M.E., Linney E. i wsp.: Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A2. Birth Defects Res. A Clin. Mol. Teratol. 2005; 73: 868‑875.
• 175. Kim H., Lapointe J., Kaygusuz G. i wsp.: The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer. Cancer Res. 2005; 65: 8118‑8124.
• 176. Niederreither K., Fraulob V., Garnier J.M. i wsp.: Differential expression of retinoic acid‑synthesizing (RALDH) enzymes during fetal development and organ differentiation in the mouse. Mech. Dev. 2002; 110: 165‑171.
• 177. Barcelo‑Coblijn G., Murphy E.J., Mills K. i wsp.: Lipid abnormalities in succinate semialdehyde dehydrogenase (Aldh5a1‑/ ‑) deficient mouse brain provide additional evidence for myelin alterations. Biochim. Biophys. Acta 2007; 1772: 556‑562.
• 178. Hogema B.M., Gupta M., Senephansiri H. i wsp.: Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat. Genet. 2001; 29: 212‑216.
• 179. Vasiliou V., Pappa A.: Polymorphisms of human aldehyde dehydrogenases. Consequences for drug metabolism and disease. Pharmacology 2000; 61: 192‑198.
• 180. Carpentino J.E., Hynes M.J., Appelman H.D. i wsp.: Aldehyde dehydrogenase‑expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Res. 2009; 69: 8208‑8215.
• 181. Ginestier C., Hur M.H., Charafe‑Jauffret E. i wsp.: ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007; 1: 555‑567.
• 182. Mukhopadhyay K.D., Bandyopadhyay A., Chang T.T. i wsp.: Isolation and characterization of a metastatic hybrid cell line generated by ER negative and ER positive breast cancer cells in mouse bone marrow. PLoS One 2011; 6: e20473.
• 183. Penumatsa K., Edassery S.L., Barua A. i wsp.: Differential expression of aldehyde dehydrogenase 1a1 (ALDH1) in normal ovary and serous ovarian tumors. J. Ovarian Res. 2010; 3: 28.

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