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Molecular genetic characterization of pediatric malignant fibrous histiocytoma

University of British Columbia

Cytogenetic and molecular genetic studies were performed on a pleiomorphic sarcoma diagnosed as malignant fibrous histiocytoma (MFH), removed from the heart of a 15 year old girl. MFH is the most common soft tissue sarcoma in adults, however, it is extremely rare in the pediatric population. Accurate pathologic classification of MFH is difficult because these primitive sarcomas lack recognizeable features of differentiation using conventional pathological techniques. Recently, analysis of chromosomal alterations in human malignancies has revealed that recurring genetic changes are often closely associated with specific subtypes of tumours, and can be useful for diagnostic and prognostic classification. To date, there are no cytogenetic alterations considered to be diagnostic for MFH. Cytogenetic analysis of the present case revealed a complex karyotype with a near-tetraploid chromosome complement and with several alterations previously reported to occur non-randomly in adult MFH, including abnormalities of chromosomal band 19pl3. Since 19pl3 aberrations are relatively common in MFH and result in 19p+ derivative chromosomes that are associated with a high relapse rate, we chose to further characterize chromosome 19 abnormalities in MFH . To investigate whether there is a chromosomal deletion in the derivative 19 chromosomes, loss of heterozygosity (LOH) studies were performed by microsatellite analysis, revealing no allelic loss (i.e. no gross deletions). Fluorescence in situ hybridization (FISH) was used to more accurately define the chromosome 19 aberrations. Using a chromosome 19 painting probe, three derivative 19 chromosomes and two normal 19 chromosomes were identified in this MFH. Dual-coloured FISH with 19q and 19p specific probes indicated that two of the extra pieces of chromosome 19 originated from 19q, and the other from 19p. Furthermore, using chromosome 4 and 19 painting probes, two t(4;19) translocation derivatives were identified, which we believe represent the two 19q derivatives. Moreover, the tumor demonstrated homogeneously staining regions (HSRs) and double minutes (dmins) suggestive of gene amplification. Genes localized to chromosomal bands 12ql3-14, including the putative proto-oncogenes MDM2, CDK4, SAS, CHOP, and GLI, are frequently amplified and overexpressed in adult MFH. We therefore screened the present case for amplification of these genes. Southern and Northern blot analysis demonstrated co-amplification of MDM2, CDK4, SAS, and CHOP. Not only do the results in this study provide cytogenetic and molecular genetic evidence that pediatric and adult MFH are histogenetically related entities, but it may also provide valuable information regarding the identification of potential tumour markers in pediatric and adult MFH.

Thesis/Dissertation

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2009-03-26

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http://hdl.handle.net/2429/6575

Pathology

University of British Columbia

UBCV

DSpace