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- Non Hodgkin Lymphome (1) (entfernen)
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Tumors of the hematopoietic and lymphoid system are classified into Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Approximately 80% of non-Hodgkin lymphomas (NHL) are B-cell lymphomas (B-NHL) and the remainder include T-cell and NK-cell lymphomas as well as immunodeficiency-associated lymphoproliferative disorders. The presence of genetic alterations such as translocations involving the immunoglobulin (Ig) receptor loci in B-NHL, e.g. the translocation t(14;18)(q32.33;q21.3) in follicular lymphoma (FL), are of great value for the classification and of importance in the pathogenesis of these neoplasms. In analogy to the Ig receptor genes in B-NHL, the T-cell receptor (TCR) gene loci are targeted by chromosomal breaks in approximately 30% of precursor T-cell lymphoblastic leukemias/lymphomas involving various translocation or inversion partners. Most of these events result in the overexpression of an oncogene by juxtaposing it to the regulatory sequences of the TCR genes. However, the pathogenesis of mature T-cell NHL (T-NHL) and the underlying molecular mechanisms are only poorly understood so far. To determine the exact frequency of breakpoints occurring in the TCR loci of 227 mature T-NHL cases, we designed fluorescence in situ hybridization (FISH) assays for the TCR loci that are applicable for large scale analysis of formalin fixed and paraffin embedded (FFPE) lymphoma specimens in a tissue microarray format. This approach revealed only two mature T-NHL cases with a chromosomal breakpoint in one of the TCR loci making the rearrangement of TCR loci a very rare event in these neoplasms that occurs in less than 1% of cases.FL is the second most frequent type of B-NHL that can show predominantly follicular, combined follicular and diffuse, or predominantly diffuse growth patterns. The characteristic genetic hallmark of FL is the translocation t(14;18)that occurs in approximately 90% of cases and leads to a deregulated expression of the anti-apoptotic BCL2 proto-oncogene. FL has yet been a subject of many studies deciphering morphological, clinical and molecular features of this entity. However, only little information exists about cases lacking this translocation. In this thesis we divided 184 FL cases by polymerase chain reaction (PCR) and by FISH assays into FL cases with and without t(14;18) and investigated their respective gene expression profiles and copy number alterations. For FISH analysis we followed the refined conditions established for the T-NHL study. The only genetic alterations that differed significantly by comparative genomic hybridization (CGH) analysis between FL cases with and without t(14;18) were frequent gains or amplifications in 18q11-q21 in 32% of t(14;18)-positive and 0% of t(14;18)-negative cases. Gene expression profiling and geneset enrichment analysis (GSEA) revealed an enrichment of germinal center B-cell (GCB) signatures in t(14;18)-positive cases whereas an enrichment of activated B-cell (ABC) like, NFkB-, proliferation-, cell cycle-, interferon and bystander cell signatures were observed in t(14;18)-negative cases. A validation approach by immunohistochemistry (IHC) on an independent test set of FL cases (n=84) revealed a more frequent expression of the germinal center (GC) marker CD10/MME in cases with t(14;18) and a higher expression of the post GC marker IRF4/MUM1, the proliferation marker Ki67 and the cytotoxic T-cell marker GZMB in cases without t(14;18). Although these results may suggest a post-GCB phenotype for translocation t(14;18)-negative cases, ongoing somatic hypermutations of the immunoglobulin heavy chain genes in these cases rather point to a late GC stage of B-cell differentiation in FL without t(14;18). In an independent study with 35 predominantly diffuse FL cases, it was furthermore possible to define another subset of t(14;18)-negative FL characterized by a chromosomal deletion (del) in 1p36 and distinct morphological and clinical features by IHC, classical chromosome banding, FISH and gene expression profiling. The gene expression profiles of predominantly diffuse FL cases fell into the spectrum of FL. However, by GSEA they showed a significant enrichment of T-cell, NK-cell- and two dendritic-cell subset signatures, whereas a significant enrichment of GCB cell-, proliferation-, cell cycle- and B-cell signatures was observed in a control group of “classic” FL cases. Remarkably, patients with diffuse FL frequently presented with low clinical stage and large, but localized inguinal tumors. In conclusion, our results suggest that t(14;18)-negative FL are part of the spectrum of FL in general, but nevertheless show distinct molecular and clinical features. In particular, predominantly diffuse FL with (del)1p36, low clinical stage and large but localized inguinal tumors may represent a distinct t(14;18)-negative FL subtype.