| The classification of tumors of the thymus has been one of the most controversial fields in tumor pathology of the last decade. These neoplasms show considerable functional, histogenetic, and morphological complexity. Recently, several major conceptional advances in the understanding of thymomas have been made and a new World Health Organization-authorized histological classification of thymic epithelial tumors emerged.Although the histopathological and immunological features of thymomas have been intensively studied, their genetic characterization has been hampered by the rare incidence and the abundant nonneoplastic lymphocytes. In particular, in contrast to many other solid tumors, the genetic background of thymoma remains unknown so far. Only little is known about genetic aberrations in thymoma. There are only few case reports of aberrant thymoma and thymic carcinoma karyotypes published in the literature. Cytogenetic studies describingthe karyotypes of these tumors are mostly case studies showing no recurrent aberrations.Various gross genetic aberrations and their association with several different thymoma types were recently depicted in a comparative genomic hybridization (CGH) study. The most prominent abnormalities described in that work were amplifications of genetic material on chromosome 1q , 17q, 18 and deletions on chromosomes 6 ,13q ,3p, 16q, and 17p in type B3 thymomas and in type C thymomas. Striking was the paucity of chromosomal abnormalities in type A thymoma. Some molecular studies have shown that inactivation of the CDKN2A (p16) and RB genes may play a role in the progression of thymoma and thymic carcinoma and that BCL-2 overexpression correlates with aggressiveness of thymic epithelial neoplasms. The high incidence of H-RAS mutations in metastatic thymomas indicates that this aberration could be used as a possible marker of aggressive behavior. Also nerve growth factor (NGF) receptors might be involved in the abnormal proliferation of neoplastic thymic epithelial cells as indicated by down-regulation of type 1 neurotrophic tyrosine kinase receptor TrkA and up-regulation of nerve growth factor receptor p75NGFR in thymic carcinomas. Therefore, less is known about specific molecular mechanisms underlying thymomagenesis and the role individual genes are playing in that process.Clearly, all these molecular studies have usually narrowly focused on the role of a particular individual gene in the pathogenesis of the disease and did not investigate the sequence and relationship between the genetic abnormalities detected. CGH study identified several nonrandom losses or gains of genetic material suggesting the presence of tumor suppressor genes or oncogenes, respectively. It identified the chromosomal regions involved, but not the individual genes.To do that, together combining with CGH, a method that can detect also amplifications or deletions in the range of tens of base pairs like microsatellite analysis has to be applied. This method has also the advantage of simultaneously detecting microsatellite instability caused by dysfunction of mismatch-repair genes recently described in epithelial cancer.Therefore, Special strategy was taken that genetic characterization was concentrated on the rare WHO types A, B3, and C that harbor few lymphocytes to avoid interference from nonneoplastic lymphocyte. In first part of our study, CGH was performed on 21 thymoma cases including types A, B3, and C tumors, to preliminarily concentrate on and narrow the hot spots of genetic imbalance (amplification and loss) of chromosomes in thymoma in order to focus the targets for analysis of allelic imbalance. In second part, we performed a limited genomic search with 51 highly informative microsatellite markers on 26 thymoma cases with data of 20 cases analyzed by CGH, including types A, B3, and C tumors, aiming to identify gene loci involved in the pathogenesis of thymomas. And also simultaneously analysis of microsatellite instability was carried out in third part. In this work, we charact...
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