Zur Bedeutung von somatischen Mutationen und Keimbahnmutationen des HMGA2 Gens bei Tumorerkrankungen
|Other Titles:||The significance of somatic mutations and germ line mutations of the HMGA2 gene in oncogenesis||Authors:||von Ahsen, Inga||Supervisor:||Bullerdiek, Jörn||1. Expert:||Bullerdiek, Jörn||2. Expert:||Wenk, Heiner||Abstract:||
As to the cytogenetic subgroup of benign mesenchymal tumors with rearrangements of the chromosomal region 12q14-15, the chromosomal alterations lead to rearrangements of the HMGA2 gene. The present thesis aims at the elucidation of the role of fusion partners of HMGA2 in tumor development and in particular refers to a molecular explanation of the same translocation t(3;12)(q27~28;q14~15) in two histologically different tumor entities, i.e. lipomas and chondroid hamartomas of the lung. The fusion transcript HMGA2-LHFP found in lipomas has not been detected in three chondroid hamartomas of the lung showing a t(12;13)(q14~15;q12~14). Expression analyses of 13 chondroid hamartomas of the lung showing t(3;12)(q27~28;q14~15) detected the same fusion transcript that was described in lipomas. These data indicate that the different histology seen in lipomas and chondroid hamartomas cannot be explained by the existence of different fusion transcripts of that type. The fusion gene LPP-HMGA2 which has been detected in one of nine lipomas was detected in eight of eleven chondroid hamartomas showing a t(3;12)(q27~28;q14~15). This indicates that in chondroid hamartomas of the lung the detected LPP-HMGA2 fusion transcript may have a significant role in pathogenesis in addition to the HMGA2-LPP fusion transcript. One lipoma with a t(3;12)(q27-28;q14-15) showing only the HMGA2-LPP transcript was analysed by FISH. The FISH analyses showed that a 170kb deletion affecting the HMGA2 gene locus was accompanying the translocation. The absence of the LPP-HMGA2 transcript can be explained by the observed deletion. Furthermore in one lipoma a new sequence named C12orf9 could be identified localized 200 kb upstream of HMGA2. The gene itself can be expressed by deletion and fusion to LPP. This describes the first LPP fusion transcript besides the LPP-HMGA2 with oncogenic potential in a mesenchymal tumor. The HMGA2-LPP transcript could be identified only in a small tumor area in one of sixty-one screened chondroid hamartomas of the lung with normal karyotype. This finding suggests that HMGA2 aberration may be a primary event in tumorgeneses of chondroid lung hamartomas. Furthermore, blood samples of normal healthy donors have been screened for possible germ line mutations leading to sequence variations of HMGA2 possibly associated with mesenchymal tumors, lipomatosis or adipositas revealed that only one of 174 analysed alleles showed a single nucleotide polymorphism i.e. a G->A exchange in position 26 of exon 1 of HMGA2. This mutation leads to an amino acid exchange in codon 9 from glycine to glutamic acid.
|Keywords:||High Mobility Group Proteine, HMGA2, LPP, benign mesenchymal tumors, lipomas, pulmonary chondroid hamartomas, single nucleotide polymorphismmas, oncogenesis||Issue Date:||2-Feb-2006||URN:||urn:nbn:de:gbv:46-diss000102436||Institution:||Universität Bremen||Faculty:||FB2 Biologie/Chemie|
|Appears in Collections:||Dissertationen|
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