GENETIC ABNORMALITIES IN UVEAL MELANOMA PDF
Preview GENETIC ABNORMALITIES IN UVEAL MELANOMA
GENETIC ABNORMALITIES IN UVEAL MELANOMA Genetische afwi jkingen in oogmelanomen Nicole Corine Naus ACKNOWLEDGEMENTS This study was supported by grants from The Dutch Foundation Fighting against Blindness. The Rotterdam Blindness Foundation, The Hague Ophthalmic Foundation and the Revolving Fund of the University Hospital Rotterdam Genetic abnormalities in uveal melanoma. I\.c. Naus Thesis Rotterdam ©N.C. Kaus. 2001 No pan of this thesis may be reproduced or transmitted in any form or by any means without permission of the author Printed by: Print Partners Ipskamp, The Netherlands Cover design: Michiel Postema GENETIC ABNORMALITIES IN UVEAL MELANOMA Genetische afwij kingen in oogmelanomen Proefschrift Ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de Rector Magnificus Prof.dr.ir. J.R. van Bemmel en volgens besluit van het College voor Promoties de openbare verdediging zal plaatsvinden op woensdag 25 april 2001 om 11.45 uur door Nicole Corine NallS geboren te Oss PROMOTIECOMMISSIE Promotor Prof.dr. D. Bootsma Overige leden Prof.dr. G. van Rij Prof. dr. A Gelli'ts van Kessel Prof.dr. P.T.V.M. deJong Co-promotoren Dr. A. de Klein Dr. G.P.M. Luyten Celui qui disperse ses regards sur tout ne voit rien ou voit mal Denis Diderot Voor pa en ma V oor Michiel CONTENTS ABBREVIATIONS 8 CHAPTERl 9 General introduction 1.1 Clinical aspects of uveal melanoma 11 1.1.1 Epidemiology 11 1.1.2 Therapy 11 1.1.3 Predisposing factors 12 1.1.4 Prognostic factors 13 1.1.5 Fine needle aspiration biopsy 14 1.2 Genetic background of uveal and cutaneous melanoma 15 1.2.1 Cytogenetic findings 15 1.2.2 Genes 18 p16/NK4, and p14ARF 20 PTEl'! 22 p53/p63/p73 23 1.3 .Aims and outline of the thesis 26 PART 1: CHROMOSOMAL ABERRATIONS IN UVEAL MELANOMA 29 CHAPTER 2 31 Concurrent loss of chromosome 1p and chromosome 3 predicts a decreased disease free survival in eye melanoma patients CHAPTER 3 41 Characterisation of compex chromosomal abnormalities in uveal melanoma by fluorescent in situ hybridisation, spectral karyotyping and comparative genomic hybridisation CHAPTER 4 51 Detection of genetic prognostic markers in uveal melanoma biopsies using fluorescent in situ hybridisation CHAPTERS 63 FISH analysis on fine needle aspiration biopsie in 3 cases of suspect uveal melanoma PART 2: MOLECULAR GENETIC ABNORMALITIES IN UVEAL 73 MELANOMA CHAPTER 6 75 Establishement and characterisation of primay and metastatic uveal melanoma cell lines CHAPTER 7 87 Methylation is the major cause of p16[},'K4fl inactivation in uveal melanoma cell lines CHAPTERS 97 Mutation analysis of the PTEN gene in uveal melanoma cell lines CHAPTER 9 105 General considerations and future prospects REFERENCES III SUMMARY & SAMENVATTING 123 COLOUR ILLUSlRATIONS 128 LIST OF PUBLICATIONS 137 CURRICULUM VITAE 140 DANKWOORD 141 ABBREVIATIONS ATM ataxia telangiectasia mutated ATR ataxia telangiectasia related BRCA2 hereditary breast and ovarian cancer gene type 2 CDK cyclin dependent kinase CDKN2A cyclin dependent kinase inhibitor 2a CGH comparative genomic hybridisation Chk2 checkpoint kinase 2 DNS dysplastic naevus syndrome EORTC European Organisation of Research and Treatment of Cancer FAK focal adhesion kinase FA.\1M\1 familial atypical multiple malignant mole syndrome FISH fluorescent in situ hybridisation FNAB fine needle aspiration biopsy lCA.'\1 intercellular cell adhesion molecule kD kilo Dalton LOH loss of heterozygosity YlDM2 murine double minute 2 :>!MAC mutated in multiple advanced cancers :\ITS] multiple tumour suppressor gene !\CA.'\1 neural cell adhesion molecule P] 4ARF. protein of 14kD, alternative reading frame of INK4A p16INK44 protein of 16 kD~ inhibitor of the cyclin dependent kinase 4A PDKI phosphonositide-dependent kinase 1 PIS-kinase phosphatidylinositol 3-0H kinase PtdIns(x,y)P phosphatilyd insolitol x.y phospohate PTEN phosphatase and tensin homolog RB retinoblastoma gene SKY spectral karyotyping TEPI TGFJ3-regulated and epithelial cell-enriched phosphatase I TNF tumour necrosis factor UV ultraviolet light 8 GENERAL INTRODUCTION
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