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FGFR3 mutations and genomic alterations as pathway determinants in the progression of non-muscle-invasive bladder cancer

Karsten Zieger  


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Accepted by: Faculty of Health Sciences Aarhus University
Defended on: December 14, 2007
Official opponents: Per Uno Malmstöm, Dept. Urology, Uppsala, Sweden , Arndt Hartmann, Dept. Pathology, Erlangen, Germany , Søren Laurberg, Dept. Surgery, Aarhus, Denmark
Tutors: Torben F. Ørntoft, prof., Dept. Clinical Biochemistry , Lars Dyrskjøt, PhD, Dept. Clinical Biochemistry , Klaus Møller-Ernst Jensen, dr.med., Dept. Urology

Published in the PhD Database: January 2, 2008


English abstract
This PhD-dissertation originates from the Molecular Diagnostic Laboratory and the Department of Urology, Aarhus University Hospital, Skejby, Denmark. The studies are based on a large tissue bank with clinical follow-up information on consecutive bladder cancers, prospectively collected since 1994 to study molecular changes of bladder cancer.
Non-muscle invasive bladder cancer is suitable for bladder-sparing, transurethral resections. However, recurrences are common, and the individual risk of progression to muscle-invasive, life threatening stages is difficult to predict. The detection of concomitant carcinoma in situ (CIS), a high-risk pre-invasive lesion is of major significance. Molecular changes may improve the clinical risk prediction. Mutations of the FGFR3 gene were recently detected in most superficial bladder polyps with a benign course. However, these mutations occur, less frequently, in progressed tumors as well.
The thesis is about the significance of FGFR3 mutations for the clinical risk prediction, and the association between FGFR3 mutations and CIS. Moreover, the impact of genome-wide chromosomal changes was investigated using single-nucleotide-polymorphism (SNP-) microarrays, which show both DNA copy alterations and allelic instability simultaneously. Finally, associations between FGFR3 mutations, CIS, and gene-expression profiles were described.
Results: FGFR3-mutations determine a molecular pathway in the development of papillary bladder tumors. However, knowledge of the mutation status did not improve the clinical risk prediction. Primary tumors with mutations never had concomitant CIS, but CIS could occur in the later course of these tumors. In contrast, concomitant CIS was frequent in primary tumors with no mutation. We found copy number gains of chromosome 5p to be markers for these tumors, and showed that gene-expression profiles were associated with the identified pathways.
Although improvement of the clinical risk prediction could not be shown, the results have considerable impact on the future use of molecular profiling in bladder cancer. In several cancer forms including bladder cancer, gene expression signatures related to molecular subgroups with different clinical outcome have been identified in the recent past, and will probably become important for the future diagnosis and choice of treatment for these cancers. The present results are based on DNA changes, and thus easily reproduced. This enables simple pathway determination with respect to treatment choice, and allows stratification of gene expression profiles into molecular subgroups. This will hopefully improve the predictive ability of these profiles regarding functional changes of tumor cell biology during the process of disease progression.



Danish abstract
Undersøgelserne til denne PhD-afhandling er udført ved Molekylært Diagnostisk Laboratorium og Urinvejskirurgisk Afdeling, Århus Universitetshospital, Skejby. Basis var en stor vævsbank med tilknyttet klinisk information om konsekutive blæretumorer, indsamlet siden 1994 med det formål at udnytte molekylære forandringer i blærekræft til at forudsige sygdommens udvikling.
Blæretumorer er blandt de hyppigste kræftsygdomme i Danmark. Ikke-muskelinvasive former er principielt egnede til transuretrale resektioner (TURB), men tilbagefald (recidiver) er almindelige og den individuelle risiko for progression (udvikling af invasiv, potentielt dødelig cancer) er klinisk svært at forudsige. Af stor betydning er påvisningen af carcinoma in-situ (CIS), et høj-risiko kræft¬forstadium, i blæren. Molekylære forandringer kan måske forbedre risikovurderingen. Mutationer i FGFR3-genet blev for nylig beskrevet i de fleste blærepolypper med et godartet forløb, men findes mindre hyppigt også i progredierende cancere.
I afhandlingen undersøges betydningen af FGFR3-mutationer for den kliniske vurdering af progres¬sionsrisikoen, samt associationen mellem FGFR3-mutationer og CIS. Herudover undersøges betydningen af kromosomale forandringer ved hjælp af single-nucleotide-polymorphism (SNP-) microarrays, som kan bestemme både DNA kopi-tals-forandringer og allel-instabilitet i hele kromosomsættet på én gang. Endvidere beskrives associationen med gen-ekspressions-profiler.
Resultaterne viser at FGFR3-mutationer kendetegner en molekylær ¿pathway¿ i udviklingen af papillomatøse blæretumorer. Mutationerne kunne imidlertid ikke bruges til at forbedre den kliniske risikovurdering. Førstegangs tumorer med FGFR3 mutation var aldrig ledsaget af CIS, men CIS kunne optræde i det senere forløb. Derimod var CIS hyppig ved primære tumorer uden mutation. Vi fandt at bl.a. kopitals-øgning af kromosom 5p kendetegner disse tumorer, og viste at deres udvik¬ling følger en anden molekylær ¿pathway¿, også hvis tumorerne har et papillomatøst vækstmønster.
Selvom en forbedring af den kliniske risikovurdering ikke blev påvist, har arbejdet dog stor betyd¬ning for den fremtidige omgang med molekylære signaturer. Gen-ekspressionsprofiler med progno¬stisk betydning er beskrevet og valideret for flere kræftformer, og kommer til at få stor betydning i fremtidens diagnostik. Resultaterne hér er baseret på DNA-forandringer, som nemt kan reproduce¬res. Hermed vil det på simpel vis være muligt ikke kun at inddele tumorerne i relevante undergrup¬per mhp. målrettet behandling, men også at stratificere tilhørende ekspressionsprofiler til forudsi¬gelse af progressionsrisikoen. Et stort valideringsarbejde ligger forud.