The Molecular Pathogenesis of Bladder Cancer

120 Pages·2011·2.94 MB·English

The Molecular Pathogenesis of Bladder Cancer
De moleculaire pathogenese van blaaskanker
Proefschrift
Ter verkrijging van de graad van Doctor
Aan de Erasmus Universi!ei! Rotterdam
Op gezag van de Rector Magnificus
Prof. Dr. Ir. J. H. van Bemmel
Volgens het beslui! van het College voor Promoties
De openbare verdediging zal plaatsvinden op
17 januari 2001 om 15.45 uur
Door
Annechiena Geertruida van Tilborg
Geboren te 's-Gravenhage
Promotie commissie:
Promotor: Prof. Dr. D. Sootsma
Prof. Dr. Th. H. van der Kwast
Co-promotor: Dr. E. C. Zwarthoff
Overige Jeden: Prof. Dr. J. W. Oosterhuis
Prof. Dr. F. H. Schroder
Prof. Dr. C. J. Cornelisse
Dit proefschrift werd bewerkt binnen de afdeling Pathologie van de Faculteit der
Geneeskunde en Gezondheidswetenschappen, Erasmus Universiteit Rotterdam.
'Wanneer je staat tegenover het numineuze dan
past aileen nederigheid. En v~~r kleine wezens zoa/s wi}
is de onmetelijke uitgestrektheid van het heelal
aileen te verdragen wanneer je Iiefhebt."
Carl Sagan - Contact
Index
List of Abbreviations 7
Chapter 1. General Introduction 9
Bladder Cancer 11
Anatomy and histology of the normal bladder 11
Epidemiology 12
Histological subgroups 12
Grading and staging 13
Clinical Presentation 13
Treatment 13
Risk Factors 14
Genetic susceptibility 15
Cancer genetics 16
Chromosomes and cancer 16
Oncogenes and tumor suppressor genes 16
Chromosomal instability 18
Microsatellite instability and LOH 20
Clonality versus field cancerization 21
Genetic aberrations in bladder cancer 22
Cytogenetic studies and CGH in bladder cancer 22
Oncogenes and tumor suppressor genes that playa role in bladder cancer 22
Loss of heterozygosity in bladder cancer 24
The role of chromosome 9 in bladder cancer 26
Outline of this thesis 28
Chapter 2. Loss of heterozygosity and loss of chromosome 9 copy number are
separate events in the pathogenesis of transitional cell carcinoma of
the bladder 31
Chapter 3. Evidence for two candidate tumor suppressor loci on chromosome
9q in transitional cell carcinoma (TCC) of the bladder but no
homozygous deletions in bladder tumor cell lines 45
Chapter 4. The chromosome 9q genes TGFBR1, TSC1 and ZNF189 are rarely
mutated in bladder cancer 57
Chapter 5. Molecular evolution of multiple recurrent cancers of the bladder 67
Chapter 6. Variable losses of chromosome 9q regions in multiple recurrent
bladder tumors prohibit the localization of a postulated tumor
suppressor gene 83
Chapter 7. General Discussion 95
Aim of this thesis 97
No correlation between underrepresentation of chromosome 9 and LOH 97
Many candidate regions but no mutant genes 98
Mitotic recombination as an explanation for multiple LOH events 98
A second look at chromosome 9q LOH: multiple recurrent bladder cancers 99
Future directions 100
Samenvatling 101
References 104
Dankwoord 115
List of publications 118
Curriculum Vitae 119

List of Abbreviations
CGH Comparative Genomic Hybridization
CIS Carcinoma in situ
DBCCR1 Deleted in Bladder Cancer Candidate Region 1
EST Expressed Sequence Tag
FAI Fractional Allelic Imbalance
FGFR3 Fibroblast Growth Factor Receptor 1
HDA Heteroduplex Analysis
ISH in situ Hybridization
LOH Loss of heterozygosity
MIN Microsatellite instability
PCR Polymerase Chain Reaction
SCE Sister Chromatid Exchange
SRO Smallest Region of Overlap
SSCP Single Strand Conformational Polymorphism
STS Sequence Tagged Site
TCC Transitional Cell Carcinoma
TGFBR1 Transforming Growth Factor Receptor 1
TUR Transurethral resection
TSC1 Tuberous Sclerosis Complex gene 1
TSG Tumor Suppressor Gene

Chapter 1. General Introduction