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Molecular pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma and related neoplasias
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is the only non-classical subtype of Hodgkin lymphoma (HL), accounting for approximately 5% of HL cases. The hallmark of HL is a low percentage of tumor cells of ≤1%, called Hodgkin Red-Sternberg (HRS) cells in cHL and lymphocyte-predominant (LP) cells in NLPHL, scattered within an abundant reactive infiltrate. In comparison to classical HL (cHL), NLPHL predominantly affects males (75%), and NLPHL patients more frequently present with early stage disease and an indolent clinical course. However, relapses and transformation into aggressive B-cell lymphomas occur more often in NLPHL. Despite the identification of some genetic factors contributing to the development of NLPHL, the molecular pathogenesis of this lymphoma entitiy is largely unsolved. Due to their rarity and the low tumor cell content primary cases of NLPHL have not been investigated yet by whole exome sequencing (WES). The aim of the present thesis was to identify molecular events and genetic factors playing a role in the pathogenesis of NLPHL as well as in its transformation process into T cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and diffuse large B-cell lymphoma (DLBCL). In the first part of this thesis, ten primary cases of NLPHL were investigated by WES to identify mutated genes that may be implicated in the pathogenesis of NLPHL. For this purpose, 3000 LP cells were laser-microdissected from frozen tissue of lymphoma patients followed by enrichment of the genomic DNA by whole genome amplification (WGA). Peripheripheral mononuclear cells (PBMCs) or microdissected non-tumor cells (NTCs) processed like the LP cells served as matched normal DNA. In order to compensate the WGA bias of randomly introduced polymerase errors, duplicate reactions of each LP cells and NTCs were sequenced, identifying somatic mutations by the presence in both LP WGA reaction and the absence in the normal DNA. Though covering a major fraction of the exome of ≥70% in the majority of cases, regions of interest ...
Molecular pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma and related neoplasias
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is the only non-classical subtype of Hodgkin lymphoma (HL), accounting for approximately 5% of HL cases. The hallmark of HL is a low percentage of tumor cells of ≤1%, called Hodgkin Red-Sternberg (HRS) cells in cHL and lymphocyte-predominant (LP) cells in NLPHL, scattered within an abundant reactive infiltrate. In comparison to classical HL (cHL), NLPHL predominantly affects males (75%), and NLPHL patients more frequently present with early stage disease and an indolent clinical course. However, relapses and transformation into aggressive B-cell lymphomas occur more often in NLPHL. Despite the identification of some genetic factors contributing to the development of NLPHL, the molecular pathogenesis of this lymphoma entitiy is largely unsolved. Due to their rarity and the low tumor cell content primary cases of NLPHL have not been investigated yet by whole exome sequencing (WES). The aim of the present thesis was to identify molecular events and genetic factors playing a role in the pathogenesis of NLPHL as well as in its transformation process into T cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and diffuse large B-cell lymphoma (DLBCL). In the first part of this thesis, ten primary cases of NLPHL were investigated by WES to identify mutated genes that may be implicated in the pathogenesis of NLPHL. For this purpose, 3000 LP cells were laser-microdissected from frozen tissue of lymphoma patients followed by enrichment of the genomic DNA by whole genome amplification (WGA). Peripheripheral mononuclear cells (PBMCs) or microdissected non-tumor cells (NTCs) processed like the LP cells served as matched normal DNA. In order to compensate the WGA bias of randomly introduced polymerase errors, duplicate reactions of each LP cells and NTCs were sequenced, identifying somatic mutations by the presence in both LP WGA reaction and the absence in the normal DNA. Though covering a major fraction of the exome of ≥70% in the majority of cases, regions of interest ...
Molecular pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma and related neoplasias
Schuhmacher, Bianca (Autor:in) / Küppers, Ralf
20.09.2019
Hochschulschrift
Elektronische Ressource
Englisch
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