Untersuchungen zur Genetik von Speicheldrüsentumoren [Elektronische Ressource] = (Genetic analyses of salivary gland tumors) / vorgelegt von André Fehr

Andre Fehr

Description

Untersuchungen zur Genetik von Speicheldrüsentumoren [Genetic Analyses of Salivary Gland Tumors] DISSERTATION zur Erlangung des Grades eines Doktors der Naturwissenschaften - Dr. rer. nat. - dem Fachbereich Biologie / Chemie der Universität Bremen vorgelegt von André Fehr Bremen, im September 2009 1. Gutachter: Prof. Dr. Jörn Bullerdiek (Bremen) 2. Gutachter: Prof. Dr. Göran Stenman (Göteborg) ”Theoreouook,heoreouind!”Robert.einberg All experimental work was done at the: Zentrum für Humangenetik University of Bremen Leobener Str. ZHG D-28359 Bremen Germany Reviewers of this thesis are: Professor Dr. Jörn Bullerdiek Zentrum für Humangenetik University of Bremen Leobener Str. ZHG D-28359 Bremen Germany and Professor Dr. Göran Stenman Department of Pathology The Sahlgrenska Academy at Göteborg University Sahlgrenska University Hospital SE-41345 Göteborg Sweden Contents Contents Summary .................................................................................................................... 2Zusammenfassung ..................................................................................................... 4List of Papers.............................................................................................................. 6Introduction...............................................................................................

Sujets

• Biologie

Informations

• Publié par: universitat_bremen
• Publié le: 01 janvier 2009
• Nombre de lectures: 46
• Langue: Deutsch
• Poids de l'ouvrage: 2 Mo

Extrait

   

 

 

Untersuchungen zur Genetik von Speicheldrüsentumoren   [Genetic Analyses of Salivary Gland Tumors]     DISSERTATION   zur Erlangung des Grades eines Doktors der Naturwissenschaften - Dr. rer. nat. -     dem Fachbereich Biologie / Chemie der Universität Bremen     vorgelegt von André Fehr

   

Bremen, im September 2009       1. Gutachter: Prof. Dr. Jörn Bullerdiek (Bremen) 2. Gutachter: Prof. Dr. Göran Stenman (Göteborg)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

”The more you look, the more you find!”

 

 

 

 

 

 

Robert A. Weinberg

  All experimental work was done at the: Zentrum für Humangenetik University of Bremen Leobener Str. ZHG D-28359 Bremen Germany

          Reviewers of this thesis are: Professor Dr. Jörn Bullerdiek Zentrum für Humangenetik University of Bremen Leobener Str. ZHG D-28359 Bremen Germany

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Professor Dr. Göran Stenman Department of Pathology The Sahlgrenska Academy at Göteborg University Sahlgrenska University Hospital SE-41345 Göteborg Sweden

Contents

Contents

  Summary .................................................................................................................... 2 Zusammenfassung ..................................................................................................... 4 List of Papers.............................................................................................................. 6 Introduction ................................................................................................................. 7 Salivary Gland Tumors .......................................................................................................... 7 Pleomorphic Adenoma ........................................................................................................... 7 Warthin’s Tumor (Cystadenolymphoma) .............................................................................. 9 Mucoepidermoid Carcinoma................................................................................................ 10 Diagnosis and Prognosis of Salivary Gland Tumors ........................................................... 12 Aims of the Thesis............................................................................................................. ... 13 Materials and Methods ............................................................................................. 14 Tumor Material and Cell Lines ............................................................................................ 14 Buffers, Solutions and Culture Media.................................................................................. 14 Kits.......................................................................................................................................15  cDNA-Synthesis and PCR...................................................................................................15  Sequencing of PCR-Products ............................................................................................... 16 In Silico Analysis ............................................................................................................. .... 16 Results ..................................................................................................................... 17 CRTC1-MAML2 Fusion in WAT (Paper I) ........................................................................ 17 CRTC1-MAML2 and HMGA2 in MEC (Papers II, III and IV) .......................................... 17 Discussion ................................................................................................................ 19 CRTC1-MAML2 Fusion in WAT (Paper I) ........................................................................ 21 CRTC1-MAML2 and HMGA2 in MEC (Papers II, III and IV) .......................................... 23 Acknowledgements .................................................................................................. 28 References ............................................................................................................... 29 Appendix................................................................................................................... 38 Abbreviations.......................................................................................................................38  Distributors................................................................................................................... ........ 39 Erklärung..............................................................................................................................40  Papers I – IV............................................................................................................. 41    

1

Summary

Summary Salivary gland tumors are a morphological very heterogeneous group of tumors. This morphological diversity in combination with the relative rareness, especially of the salivary gland carcinomas makes these tumors to a major challenge for pathologists, also for those specialized to these tumors. In the recent years molecular biomarkers become increasingly important, in order to facilitate the work of the pathologist and the treating clinician. Aim of this work was to analyze the recently for mucoepidermoid carcinoma (MEC) and Warthin's tumor (WAT) described gene fusionCRTC1-MAML2for its diagnostic potential as biomarker and to find out if an aberrantHMGA2 expression level influence tumorgenesis of MECs. For this thesis we have tested approximately 140 MECs and 50 WATs for theCRTC1-MAML2 and checked for correlations fusion between fusion status and patient data. Furthermore, we have analyzed approximately 60 MECs for theirHMGA2-expression level, by real-time PCR. Our studies have shown that aCRTC1-MAML2test could be a powerful tool for diagnosis and prognosis of MECs. The fusion correlates with a low- or intermediate- grade of the tumor and is associated with a favorable prognosis. Interestingly, CRTC1-MAML2negative tumors were mainly found in high-grade tumors and show a significant increasedHMGA2 and a poor prognosis. These data raise doubts level about the correct classification of MECs into low-, intermediate- and high-grade tumors. In our opinion the present classification of MECs includes two subgroups: A huge group of “true-MECs” (ca. 70% of the tumors) with theCRTC1-MAML2   fusion, with a moderate aggressiveness and an excellent prognosis and furthermore a smaller group of morphological heterogeneous high-grade tumors lacking this fusion and with an aberrantly highHMGA2 expression level. We suggest that this “non-MEC” group comprised not only one specific tumor type.In fact it seems to be a mix of different tumor types, all poorly differentiated with typical high-grade features. Based on these studies, we approve that all MECs should be analyzed for the CRTC1-MAML2 fusion in the future routinely. In particular in border cases (intermediate vs. high-grade) the test may be very useful to do correct diagnosis.   Our study shows that theCRTC1-MAML2fusion seems to be a rare event in WATs. These fusion positive tumors are indicated for a potential malignant transformation. In

2

Summary

this field further studies are recommended. Nevertheless, we give advice to test WAT for the presence ofCRTC1-MAML2 monitoring patients with this fusion more and closely; analogous to follow-up practices for other salivary gland adenomas at risk for recurrence or progression diseases.     Key Words: Mucoepidermoid carcinoma, Warthin’s tumor,CRTC1-MAML2,HMGA2, molecular biomarker, prognostic significance

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