Dokument: Molekulare Analyse von Tumorsuppressorgen-Kandidaten auf Chromosom 10 in Tumoren des Nervensystems
| Titel: | Molekulare Analyse von Tumorsuppressorgen-Kandidaten auf Chromosom 10 in Tumoren des Nervensystems | |||||||
| Weiterer Titel: | molecular analysis of tumour suppressor gene - candidates on chromosome 10 in tumours of the nervous system | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=4259 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20070411-115659-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Köhler, Benjamin [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Prof. Dr. Reifenberger, Guido [Betreuer/Doktorvater] Prof. Dr. Sabel, Michael C. [Gutachter] PD Dr. Stege, Helge [Gutachter] | |||||||
| Stichwörter: | Glioblastom, Meningeom, Medulloblastom, Basalzellkarzinom, Chromosom 10, KLF 6, SUFU, | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Deletionen des Chromosoms 10 stellen eine häufige Veränderung in unterschiedlichen Tumoren des Nervensystems dar. Sie finden sich u.a. in der Mehrzahl der Glioblastome, aber auch in Subgruppen von atypischen und anaplastischen Meningeomen sowie Medulloblastomen. Der häufige Verlust von genetischem Material dieses Chromosoms spricht dafür, dass hier wichtige, bislang noch unbekannte Tumorsuppressorgene lokalisiert sind, deren Inaktivierung von ursächlicher Bedeutung für das Tumorwachstum der genannten Tumorentitäten ist. Erstes Ziel der eigenen Arbeit war es, im Rahmen eines sogenannten Kandidatengenansatzes die mögliche Bedeutung von genetischen Veränderungen des Tumorsuppressorgens KLF6 (10p15.2) in Glioblastomen und Meningeomen abzuklären. Ein zweiter Projektteil beschäftigte sich mit der molekularen Analyse eines anderen Kandidatengens, SUFUH (10q24.32), in Medulloblastomen und Basalzellkarzinomen der Haut. Der dritte Teil der Arbeit betraf die Identifizierung neuer Kandidatengene auf Chromosom 10, die durch DNA-Hypermethylierung in Glioblastomzellen inaktiviert sind. Hierzu wurden Mikroarray-basierte Expressionsanalysen an fünf Glioblastomzelllinien vor und nach Behandlung mit der demethylierenden Substanz 5-Aza-2’-Deoxycytidin und dem Histondeacytelase-Inhibitor Trichostatin A durchgeführt.
Die Mutationsanalyse von KLF6 in 42 Glioblastomen und 47 Meningeomen erbrachte lediglich genetische Polymorphismen aber keine tumorassoziierten Mutationen. Zusätzlich an 39 Glioblastomen und 31 Meningeomen durchgeführte mRNA-Expressionanalysen zeigten keine wesentlichen Veränderungen in Glioblastomen, wohingegen in immerhin 19 von 31 Meningeomen (61%) im Verhältnis zu normalem menigealem Gewebe um mehr als 50% verminderte KLF6-Transkriptlevel nachweisbar waren. Die molekularen Ursachen dieser erniedrigten Expression sind allerdings noch unklar. Eine aberrante DNA-Hypermethylierung konnte durch Sequenzierung des KLF6-Promotor nach Natriumbisulfit-Behandlung der DNA ausgeschlossen werden. Mutationsanalysen des SUFUH-Gens in 14 Medulloblastomen und 32 Basalzellkarzinomen deckten einen genetischen Polymorphismus im Exon 11 in sieben Medulloblastomen und drei Basalzellkarzinomen auf. Weiterhin konnten eine Missense-Mutation sowie eine stille Mutation im Exon 4 in zwei Basalzellkarzinomen nachgewiesen werden. Durch die Mikroarray-Analyse von fünf Glioblastomzelllinien vor und nach Behandlung mit 5-Aza-2’-Deoxycytidin und Trichostatin A gelang es, 25 Gene auf Chromosom 10 zu identifizieren, die nach der Behandlung eine signifikant verstärkte Expression zeigten. Anschließende Untersuchungen von vier dieser Gene mittels Real-time reverser Transkriptase-PCR bestätigten die Mikroarray-Daten. Insgesamt sprechen die eigenen Ergebnisse dafür, dass KLF6-Mutationen in der Pathogenese von Glioblastomen und Meningeomen keine wesentliche Rolle spielen. Gleiches gilt für SUFUH-Mutation in Medulloblastomen und Basalzellkarzinomen. Die Suche nach den jeweils relevanten Tumorsuppressorgenen auf Chromosom 10 muss demnach fortgeführt werden. Diesbezüglich sind die in den eigenen Arbeiten in Glioblastomzelllinien identifizierten neuen, möglicherweise epigenetisch inaktivierten Kandidatengene von großem Interesse für weitergehende Forschungsarbeiten. | |||||||
| Quelle: | Antequera F, Bird A. Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11995-9.
Bailey P, Cushing H: A Classification of the Tumors of the Glioma Group on a Histogenetic Basis with a Correlated Study of Prognosis. Philadelphia: JB Lippincott, 1926 Bayani J, Zielenska M, Marrano P, Kwan Ng Y, Taylor MD, Jay V, Rutka JT, Squire JA. Molecular cytogenetic analysis of medulloblastomas and supratentorial primitive neuroectodermal tumors by using conventional banding, comparative genomic hybridization, and spectral karyotyping. J Neurosurg. 2000 Sep;93(3):437-48. Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM, Beachy PA. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science. 2002 Aug 30;297(5586):1559-61. Bieker JJ. Kruppel-like factors: three fingers in many pies. J Biol Chem. 2001 Sep 14;276(37):34355-8. Epub 2001 Jul 6. Bigner SH, Mark J, Friedman HS, Biegel JA, Bigner DD. Structural chromosomal abnormalities in human medulloblastoma. Cancer Genet Cytogenet. 1988 Jan;30(1):91-101. Bigner SH, McLendon RE, Fuchs H, McKeever PE, Friedman HS. Chromosomal characteristics of childhood brain tumors. Cancer Genet Cytogenet. 1997 Sep;97(2):125-34. Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986 ; 321: 209-13. Bishop JM. Molecular themes in oncogenesis. Cell. 1991 Jan 25;64(2):235-48. Review. Bogler O, Huang HJ, Cavenee WK. Loss of wild-type p53 bestows a growth advantage on primary cortical astrocytes and facilitates their in vitro transformation. Cancer Res. 1995 Jul 1;55(13):2746-51. Boström J, Cobbers JM, Wolter M, Tabatabai G, Weber RG, Lichter P, Collins VP, Reifenberger G. Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Cancer Res. 1998 Jan 1;58(1):29-33. Büschges R, Weber RG, Actor B, Lichter P, Collins VP, Reifenberger G. Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas. Brain Pathol. 1999 Jul;9(3):435-42; discussion 432-3. Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998 Oct 7;90(19):1473-9. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R, Soltoff S. Oncogenes and signal transduction. Cell. 1991 Jan 25;64(2):281-302. Review. Chuang PT, McMahon AP. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature. 1999 Feb 18;397(6720):617-21. Chen C, Hyytinen ER, Sun X, Helin HJ, Koivisto PA, Frierson HF Jr, Vessella RL, Dong JT. Deletion, mutation, and loss of expression of KLF6 in human prostate cancer. Am J Pathol. 2003 Apr;162(4):1349-54. Chunduru S, Kawami H, Gullick R, Monacci WJ, Dougherty G, Cutler ML. Identification of an alternatively spliced RNA for the Ras suppressor RSU-1 in human gliomas. J Neurooncol. 2002 Dec;60(3):201-11. Collins VP. Brain tumours: classification and genes, J Neurol Neurosurg Psychiatry 2004;75(Suppl II):ii2-ii11 Collins VP. Progression as exemplified by human astrocytic tumors. Semin Cancer Biol. 1999 Aug;9(4):267-76. Costello JF, Plass C, Arap W, Chapman VM, Held WA, Berger MS, Su Huang HJ, Cavenee WK. Cyclin-dependent kinase 6 (CDK6) amplification in human gliomas identified using two-dimensional separation of genomic DNA. Cancer Res. 1997 Apr 1;57(7):1250-4. Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sorensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD, Pietsch T. Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res. 2001 Oct 1;61(19):7039-43. Dumanski JP, Carlbom E, Collin VP, Nordenskjold M. Deletion mapping of a locus on human chromosome 22 involved in oncogenesis of meningioma. Proc Natl Acad Sci U S A 1987;84:9275-79 Eberhart CG, Tihan T, Burger PC. Nuclear localization and mutation of beta-catenin in medulloblastomas. J Neuropathol Exp Neurol. 2000 Apr;59(4):333-7. Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 2000 Nov 9;343(19):1350-4. Erratum in: N Engl J Med 2000 Dec 7;343(23):1740. Fujisawa H, Kurrer M, Reis RM, Yonekawa Y, Kleihues P, Ohgaki H. Acquisition of the glioblastoma phenotype during astrocytoma progression is associated with loss of heterozygosity on 10q25-qter. Am J Pathol. 1999 Aug;155(2):387-94. Fults D, Petronio J, Noblett BD, Pedone CA. Chromosome 11p15 deletions in human malignant astrocytomas and primitive neuroectodermal tumors. Genomics. 1992 Nov;14(3):799-801. Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, Toftgard R. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996 Sep;14(1):78-81. Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW, Ehrlich M. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 1983 Oct 11;11(19):6883-94. Greger V, Debus N, Lohmann D, Hopping W, Passarge E, Horsthemke B. Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma. Hum Genet. 1994 Nov;94(5):491-6. Gusella JE, Ramesh V, MacCollin M, Jacoby LB. Merlin: The neurofibromatosis 2 tumor suppressor. Biochim Biophys Acta 1999;1423:M29-M36 Halatsch ME, Schmidt U, Behnke-Mursch J, Unterberg A, Wirtz CR. Epidermal growth factor receptor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumours. Cancer Treat Rev. 2006 Apr;32(2):74-89. Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leucemia. Blood. 1993. 82:1820-28 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70. Review. Hayashi K, Yandell DW. How sensitive is PCR-SSCP? Hum Mutat. 1993;2(5):338-46. Review. Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM, et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma.Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9700-4. Hogan DJ, To T, Gran L, Wong D, Lane PR. Risk factors for basal cell carcinoma. Int J Dermatol. 1989 Nov;28(9):591-4. Holland, E.C. Gliomagenesis:genetic alterations and mouse models. Nat Rev Genet. 2001 Feb;2(2):120-9. Ichimura K, Bolin MB, Goike HM, Schmidt EE, Moshref A, Collins VP. Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities.Cancer Res. 2000 Jan 15;60(2):417-24. Ichimura K, Schmidt EE, Miyakawa A, Goike HM, Collins VP. Distinct patterns of deletion on 10p and 10q suggest involvement of multiple tumor suppressor genes in the development of astrocytic gliomas of different malignancy grades. Genes Chromosomes Cancer. 1998 May;22(1):9-15. Ishii S. Costal-2: a scaffold for kinases mediates Hedgehog signaling. Dev Cell. 2005 Feb;8(2):140-1. Ito G, Uchiyama M, Kondo M, Mori S, Usami N, Maeda O, Kawabe T, Hasegawa Y, Shimokata K, Sekido Y. Kruppel-like factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells. Cancer Res. 2004 Jun 1;64(11):3838-43. James CD, Carlbom E, Dumanski JP, Hansen M, Nordenskjold M, Collins VP, Cavenee WK. Clonal genomic alterations in glioma malignancy stages. Cancer Res. 1988 Oct 1;48(19):5546-51. Jeng YM, Hsu HC. KLF6, a putative tumor suppressor gene, is mutated in astrocytic gliomas. Int J Cancer. 2003 Jul 10;105(5):625-9. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002 Jun;3(6):415-28. Review. Karpf AR, Jones DA. Reactivating the expression of methylation silenced genes in human cancer. Oncogene. 2002 Aug 12;21(35):5496-503. Review. Kimmelman AC, Qiao RF, Narla G, Banno A, Lau N, Bos PD, Nunez Rodriguez N, Liang BC, Guha A, Martignetti JA, Friedman SL, Chan AM. Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6. Oncogene. 2004 Jun 24;23(29):5077-83. Kisseljova NP, Kisseljov FL. DNA demethylation and carcinogenesis. Biochemistry (Mosc). 2005 Jul;70(7):743-52. Review. Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol. 2002 Mar;61(3):215-25; discussion 226-9. Review. Knippers R. Molekulare Genetik. 8. Auflage. Georg Thieme Verlag. 2001 Knobbe CB, Reifenberger G. Genetic alterations and abberant expression of genes related to the phosphatidyl-inositol-3`-kinase/protein kinase B (Akt) signal transduction pathway in glioblastoma. Brain Pathol 2003;13:507-18 Knobbe CB, Reifenberger J, Reifenberger G. Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta Neuropathol (Berl). 2004 Dec;108(6):467-70. Epub 2004 Oct 28. Knudson AG. Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol. 1996;122(3):135-40. Review. Koch A, Waha A, Hartmann W, Milde U, Goodyer CG, Sorensen N, Berthold F, Digon-Sontgerath B, Kratzschmar J, Wiestler OD, Pietsch T. No evidence for mutations or altered expression of the Suppressor of Fused gene (SUFU) in primitive neuroectodermal tumours. Neuropathol Appl Neurobiol. 2004 Oct;30(5):532-9. Köhler B, Wolter M, Blaschke B, Reifenberger G. Absence of mutations in the putative tumor suppressor gene KLF6 in glioblastomas and meningiomas. Int J Cancer. 2004 Sep 10;111(4):644-5. Koivisto PA, Zhang X, Sallinen SL, Sallinen P, Helin HJ, Dong JT, Van Meir EG, Haapasalo H, Hyytinen ER. Absence of KLF6 gene mutations in human astrocytic tumors and cell lines. Int J Cancer. 2004 Sep 10;111(4):642-3. Krishnan V, Elberg G, Tsai MJ, Tsai SY. Identification of a novel sonic hedgehog response element in the chicken ovalbumin upstream promoter-transcription factor II promoter. Mol Endocrinol. 1997 Sep;11(10):1458-66. Laird PW. The power and the promise of DNA methylation markers. Nature Reviews Cancer, Volume 3, April 2003, 253-266 Laird PW, Jaenisch R. The role of DNA methylation in cancer genetic and epigenetics. Annu Rev Genet. 1996;30:441-64. Review. Lam CW, Leung CY, Lee KC, Xie J, Lo FM, Au TS, Tong SF, Poon MK, Chan LY, Luk NM. Novel mutations in the PATCHED gene in basal cell nevus syndrome. Mol Genet Metab. 2002 May;76(1):57-61. Lamszus K. Meningioma Pathology, Genetics and Biology, J Neuropathol Exp Neurol 2004;63:275-286 Land H, Parada LF, Weinberg RA. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983 Aug 18-24;304(5927):596-602. Lasko D, Cavenee W, Nordenskjold M. Loss of constitutional heterozygosity in human cancer. Annu Rev Genet. 1991;25:281-314. Review. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002 Sep;3(9):662-73. Review. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992 Jun 12;69(6):915-26. Liang BC, Ross DA, Greenberg HS, Meltzer PS, Trent JM. Evidence of allelic imbalance of chromosome 6 in human astrocytomas. Neurology. 1994 Mar;44(3 Pt 1):533-6. Lusis EA, Watson MA, Chicoine MR, Lyman M, Roerig P, Reifenberger G, Gutmann DH, Perry A. Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res. 2005 Aug 15;65(16):7121-6. Maillo A, Orfao A, Sayagues JM, Diaz P, Gomez-Moreta JA, Caballero M, Santamarta D, Santos-Briz A, Morales F, Tabernero MD. New classification scheme for the prognostic stratification of meningioma on the basis of chromosome 14 abnormalities, patient age, and tumor histopathology. J Clin Oncol. 2003 Sep 1;21(17):3285-95. Meng X, Poon R, Zhang X, Cheah A, Ding Q, Hui C, Alman B. Suppressor of Fused negatively regulates β-Catenin signalling. J Bio Chem 2001; 276(43):40113-19 Menon AG, Rutter JL, von Sattel JP, Synder H, Murdoch C, Blumenfeld A, Martuza RL, von Deimling A, Gusella JF, Houseal TW. Frequent loss of chromosome 14 in atypical and malignant meningioma: identification of a putative 'tumor progression' locus. Oncogene. 1997 Feb 6;14(5):611-6. Merlo A. Genes and pathways driving glioblastomas in humans and murine disease models. Neurosurg Rev. 2003 Jul;26(3):145-58. Epub 2003 May 29. Review. Méthot N, Basler K. Suppressor of Fused opposes Hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development. 2000 Sep;127(18):4001-10 Michiels EM, Oussoren E, Van Groenigen M, Pauws E, Bossuyt PM, Voute PA, Baas F. Genes differentially expressed in medulloblastoma and fetal brain. Physiol Genomics. 1999 Aug 31;1(2):83-91. Michiels EM, Weiss MM, Hoovers JM, Baak JP, Voute PA, Baas F, Hermsen MA. Genetic alterations in childhood medulloblastoma analyzed by comparative genomic hybridization. J Pediatr Hematol Oncol. 2002 Mar-Apr;24(3):205-10. Mihaila D, Jankowski M, Gutierrez JA, Rosenblum ML, Newsham IF, Bogler O, Rempel SA; NABTT CNS Consortium. Meningiomas: loss of heterozygosity on chromosome 10 and marker-specific correlations with grade, recurrence, and survival. Clin Cancer Res. 2003 Oct 1;9(12):4443-51. Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J Am Acad Dermatol. 1994 May;30(5 Pt 1):774-8 Miller LD, Long PM, Wong L, Mukherjee S, McShane LM, Liu ET. Optimal gene expression analysis by microarrays. Cancer Cell. 2002 Nov;2(5):353-61. Review. Miller SJ. Etiology and pathogenesis of basal cell carcinoma. Clin Dermatol. 1995 Nov-Dec;13(6):527-36. Review. Mollenhauer J, Wiemann S, Scheurlen W, Korn B, Hayashi Y, Wilgenbus KK, von Deimling A, Poustka A. DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3-26.1 is deleted in malignant brain tumours. Nat Genet. 1997 Sep;17(1):32-9. Montanini L, Bissola L, Finocchiaro G. KLF6 is not the major target of chromosome 10p losses in glioblastomas. Int J Cancer. 2004 Sep 10;111(4):640-1. Mühlbauer KR, Gröne HJ, Ernst T, Gröne E, Tschada R, Hergenhahn M, Hollstein M. Analysis of human prostate cancers and cell lines for mutations in the TP53 and KLF6 tumour suppressor genes. Br J Cancer. 2003 Aug 18;89(4):687-90. Nakamura H, Yoshida M, Tsuiki H, Ito K, Ueno M, Nakao M, Oka K, Tada M, Kochi M, Kuratsu J, Ushio Y, Saya H. Identification of a human homolog of the Drosophila neuralized gene within the 10q25.1 malignant astrocytoma deletion region. Oncogene 1998 Feb 26;16(8):1009-19. Narla G, Friedman SL, Martignetti JA. Kruppel cripples prostate cancer: KLF6 progress and prospects. Am J Pathol. 2003 Apr;162(4):1047-52. Narla G, Heath KE, Reeves HL, Li D, Giono LE, Kimmelman AC, Glucksman MJ, Narla J, Eng FJ, Chan AM, Ferrari AC, Martignetti JA, Friedman SL. KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science. 2001 Dec 21;294(5551):2563-6. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23-8. Nüsslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980 Oct 30;287(5785):795-801. Ogden SK, Ascano M Jr, Stegman MA, Robbins DJ. Regulation of Hedgehog signaling: a complex story. Biochem Pharmacol. 2004 Mar 1;67(5):805-14. Paces-Fessy M, Boucher D, Petit E, Paute-Briand S, Blanchet-Tournier MF. The negative regulator of Gli, Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins. Biochem J. 2004 Mar 1;378(Pt 2):353-62 Paz MF, Fraga MF, Avila S, Guo M, Pollan M, Herman JG, Esteller M. A systematic profile of DNA methylation in human cancer cell lines. Cancer Res. 2003 Mar 1;63(5):1114-21. Perry A, Gutmann DH, Reifenberger G. Molecular pathogenesis of meningiomas. J Neurooncol. 2004 Nov;70(2):183-202. Review. Pietsch T, Waha A, Koch A, Kraus J, Albrecht S, Tonn J, Sorensen N, Berthold F, Henk B, Schmandt N, Wolf HK, von Deimling A, Wainwright B, Chenevix-Trench G, Wiestler OD, Wicking C. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 1997 Jun 1;57(11):2085-8 Pulst S-M, Reifenberger G. Primary Tumors of the Nervous System. In Neurogenetics. Pulst SM (Ed.), Oxford University Press, New York, Oxford, 2000, pp131-161 Quach N, Goodman MF, Shibata D. In vitro mutation artifacts after formalin fixation and error prone translesion synthesis during PCR. BMC Clin Pathol. 2004 Feb 12;4(1):1. Rao PM, Antony A, Rajalakshmi S, Sarma DS. Studies on hypomethylation of liver DNA during early stages of chemical carcinogenesis in rat liver.Carcinogenesis. 1989 May;10(5):933-7. Rasheed BK, McLendon RE, Friedman HS, Friedman AH, Fuchs HE, Bigner DD, Bigner SH. Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25. Oncogene. 1995 Jun 1;10(11):2243-6 Reddel RR, Bryan TM, Colgin LM, Perrem KT, Yeager TR. Alternative lengthening of telomeres in human cells. Radiat Res. 2001 Jan;155(1 Pt 2):194-200. Review. Reeves HL, Narla G, Ogunbiyi O, Haq AI, Katz A, Benzeno S, Hod E, Harpaz N, Goldberg S, Tal-Kremer S, Eng FJ, Arthur MJ, Martignetti JA, Friedman SL. Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer. Gastroenterology. 2004 Apr;126(4):1090-103. Reifenberger J. [Hereditary tumor syndromes. Cutaneous manifestations and molecular pathogenesis of Gorlin and Cowden syndromes] Hautarzt. 2004 Oct;55(10):942-51. Review. German Reifenberger J, Arnold N, Kiechle M, Reifenberger G, Hauschild A. Coincident PTCH and BRCA1 germline mutations in a patient with nevoid basal cell carcinoma syndrome and familial breast cancer. J Invest Dermatol. 2001 Mar;116(3):472-4. Reifenberger J, Ring GU, Gies U, Cobbers L, Oberstrass J, An HX, Niederacher D, Wechsler W, Reifenberger G. Analysis of p53 mutation and epidermal growth factor receptor amplification in recurrent gliomas with malignant progression. J Neuropathol Exp Neurol. 1996 Jul;55(7):822-31. Reifenberger J, Wolter M, Knobbe CB, Kohler B, Schonicke A, Scharwachter C, Kumar K, Blaschke B, Ruzicka T, Reifenberger G. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol. 2005 Jan;152(1):43-51. Reifenberger J, Wolter M, Weber RG, Megahed M, Ruzicka T, Lichter P, Reifenberger G. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1998 May 1;58(9):1798-803. Rempel SA, Schwechheimer K, Davis RL, Cavenee WK, Rosenblum ML. Loss of heterozygosity for loci on chromosome 10 is associated with morphologically malignant meningioma progression. Cancer Res. 1993 May 15;53(10 Suppl):2386-92. Renan MJ. How many mutations are required for tumorigenesis? Implications from human cancer data. Mol Carcinog. 1993;7(3):139-46. Robertson KD, Wolffe AP. DNA methylation in health and disease. Nat Rev Genet. 2000 Oct;1(1):11-9. Review. Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med. 2005 Nov 24;353(21):2262-9. Review. Rubin JB, Rowitch DH. Medulloblastoma: a problem of developmental biology. Cancer Cell. 2002 Jul;2(1):7-8. Ruel L, Rodriguez R, Gallet A, Lavenant-Staccini L, Thérond PP. Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nat Cell Bio 2003;5(10):907-13 Ruiz i Altaba A, Palma V, Dahmane N. Hedgehog-Gli signalling and the growth of the brain. Nat Rev Neurosci. 2002 Jan;3(1):24-33. Review. Saldanha G, Fletcher A, Slater DN. Basal cell carcinoma: a dermatopathological and molecular biological update. Br J Dermatol 2003;148:195-202 Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463-7. Sasaki H, Zlatescu MC, Betensky RA, Ino Y, Cairncross JG, Louis DN. PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis.Am J Pathol. 2001 Jul;159(1):359-67. Schmidt EE, Ichimura K, Goike HM, Moshref A, Liu L, Collins VP. Mutational profile of the PTEN gene in primary human astrocytic tumors and cultivated xenografts. J Neuropathol Exp Neurol. 1999 Nov;58(11):1170-83. Seizinger BR, de la Monte S, Atkins L, Gusella JF, Mertuza RL. Molecular genetic approach to human meningeoma: Loss of genes on chromosome 22, Proc Natl Acad Sci U S A 1987;84:5419-23 Shen JC, Rideout WM 3rd, Jones PA. The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA.Nucleic Acids Res. 1994 Mar 25;22(6):972-6. Simell O, Takki K. Raised plasma-ornithine and gyrate atrophy of the choroid and retina. Lancet. 1973 May 12;1(7811):1031-3. Situm M, Levanat S, Crnic I, Pavelic B, Macan D, Grgurevic J, Mubrin-Koncar M, Lipozencic J. Involvement of patched (PTCH) gene in Gorlin syndrome and related disorders: three family cases. Croat Med J. 1999 Dec;40(4):533-8. Somerville RP, Chernova O, Liu S, Shoshan Y, Cowell JK. Identification of the promoter, genomic structure, and mouse ortholog of LGI1. Mamm Genome. 2000 Aug;11(8):622-7. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997 Apr;15(4):356-62. Stone DM, Murone M, Luoh S, Ye W, Armanini MP, Gurney A, Phillips H, Brush J, Goddard A, de Sauvage FJ, Rosenthal A. Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli. J Cell Sci. 1999 Dec;112 ( Pt 23):4437-48. Tabatabai G, Boström J, Wolter M, Weber RG, Lichter P, Collins VP, Reifenberger G. Analysis of MXI1 candidate tumor suppressor gene for mutation and expression in glioblastomas and meningiomas. Clin Neuropathol 1998;17:249 Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002 Jul;31(3):306-10. Epub 2002 Jun 17. Tautz D, Renz M. Simple sequences are ubiquitous repetitive components of eukaryotic genomes. Nucleic Acids Res. 1984 May 25;12(10):4127-38. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003 Oct 23;425(6960):851-6. Epub 2003 Sep 14. Toftgard, R. Hedgehog signalling in cancer. Cell. Mol. Life Sci., 57:1720-1731, 2000. Ueda K, Arakawa H, Nakamura Y. Dual-specificity phosphatase 5 (DUSP5) as a direct transcriptional target of tumor suppressor p53. Oncogene. 2003 Aug 28;22(36):5586-91. Unden AB, Holmberg E, Lundh-Rozell B, Stahle-Backdahl M, Zaphiropoulos PG, Toftgard R, Vorechovsky I. Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation. Cancer Res. 1996 Oct 15;56(20):4562-5. Varmus H, Weinberg RA. Gene und Krebs. Spektrum Verlag, 1994 Heidelberg Vasaturo F, Dougherty GW, Cutler ML. Ectopic expression of Rsu-1 results in elevation of p21CIP and inhibits anchorage-independent growth of MCF7 breast cancer cells. Breast Cancer Res Treat. 2000 May;61(1):69-78. Vorechovsky I, Benediktsson KP, Toftgard R. The patched/hedgehog/smoothened signalling pathway in human breast cancer: no evidence for H133Y SHH, PTCH and SMO mutations. Eur J Cancer. 1999 May;35(5):711-3. Walsh CP, Chaillet JR, Bestor TH. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet. 1998 Oct;20(2):116-7. Watkins DN, Berman DM, Baylin SB. Hedgehog signaling: progenitor phenotype in small-cell lung cancer. Cell Cycle. 2003 May-Jun;2(3):196-8. Review. Watkins DN, Peacock CD. Hedgehog signalling in foregut malignancy. Biochem Pharmacol. 2004 Sep 15;68(6):1055-60. Review. Weber JL, May PE. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet. 1989 Mar;44(3):388-96. Weber RG, Bostrom J, Wolter M, Baudis M, Collins VP, Reifenberger G, Lichter P. Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14719-24. Wechsler-Reya R, Scott MP. The developmental biology of brain tumors. Annu Rev Neurosci. 2001;24:385-428. Review. Williams C, Ponten F, Moberg C, Soderkvist P, Uhlen M, Ponten J, Sitbon G, Lundeberg J. A high frequency of sequence alterations is due to formalin fixation of archival specimens. Am J Pathol. 1999 Nov;155(5):1467-71. Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1997 Jul 1;57(13):2581-5 Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2965-9. Xie J, Johnson RL, Zhang X, Bare JW, Waldman FM, Cogen PH, Menon AG, Warren RS, Chen LC, Scott MP, Epstein EH Jr. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 1997 Jun 15;57(12):2369-72. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage FJ. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998 Jan 1;391(6662):90-2. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Bezug: | Der praktische Teil der Dissertation wurde im Institut für Neuropathologie der Heinrich-Heine-Universität Düsseldorf durchgeführt. Die Arbeit wurde im August 2002 aufgenommen und dauerte bis zum Juni 2006 an. | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Neuropathologie | |||||||
| Dokument erstellt am: | 11.04.2007 | |||||||
| Dateien geändert am: | 11.04.2007 | |||||||
| Promotionsantrag am: | 18.07.2006 | |||||||
| Datum der Promotion: | 15.03.2007 |
