University dissertation from Dept of Clinical Genetics

Abstract: The focus of this thesis was to study cytogenetic and molecular genetic aberrations in lipomas. For this purpose, chromosome banding analysis, fluorescence in situ hybridization (FISH), as well as high resolution single nucleotide polymorphism (SNP)–arrays were used to identify recurrent chromosomal aberrations in lipomas. The possible molecular targets for these aberrations were further studied through conventional and quantitative polymerase chain reaction (PCR and qRT-PCR) analyses and global gene expression profiling. Lipomas were found to be characterized by recurrent chromosome aberrations, frequently involving the HMGA2 gene. Furthermore, HMGA2 was found to be differentially expressed in different cytogenetic and morphologic subgroups of adipocytic tumors, with the highest expression levels occurring in atypical lipomatous tumor / well differentiated liposarcoma; these tumors usually have amplification, in the form of supernumerary ring chromosomes, of the chromosomal region where the HMGA2 gene is located. The second highest expression levels of HMGA2 were seen in conventional lipomas with structural rearrangements of chromosome region 12q13-15. Tumors expressing the full-length gene did not express the 3’ untranslated region (3’UTR), suggesting that the aberrant HMGA2 expression of the full-length gene was due to loss of regulatory sequences in the 3’UTR. Another frequent cytogenetic aberration in conventional lipomas was deletion of the long arm of chromosome 13. Using SNP-arrays, this deletion could be further delineated. Two minimal deleted regions (MDR) in chromosome band 13q14 were found in spindle cell lipomas (SCLs) and one in conventional lipomas; the latter MDR overlapped with one of those in SCLs. By global gene expression analysis and qRT-PCR one gene, C13orf1, was found to be expressed at significantly lower levels in conventional lipomas, and one microRNA (miR-16-1) turned out to be a potential target in SCLs. Further studies are needed to validate if the functional outcome of the 13q-deletions is loss of one or both of these genes.

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