Molecular cytogenetic characterization of chromosome aberrations in soft tissue and bone tumors

Abstract: Bone and soft tissue tumors (BSTT) belong to a diverse group of solid tumors of mesenchymal origin, with a large number of histological types affecting individuals of all ages. The general aim of the present thesis (Articles I-V) was to investigate in detail the genetic aberrations in selected subtypes of benign and malignant BSTT. Aberrations identified by chromosome banding analysis were studied in more detail by molecular techniques, in particular by FISH. I: The results demonstrate that the frequent chromosome 1 breakpoints in tenosynovial giant cell tumors are clustered to a common region in chromosome subband 1p13.2, indicating that this segment contains a gene that through dysregulation or formation of a fusion gene plays a role in the tumorigenesis. Chromosome 2 was the most frequent translocation partner. The breakpoints in 2q35-37 were less clustered than the chromosome 1 breakpoints, but were at least in four cases localized together in a sequence where the G protein-coupled receptor gene CMKOR1 is located. II: The finding of t(1;17)(q32;q21) as a characteristic, recurrent and probably pathogenetically significant aberration in bizarre parosteal osteochondromatous proliferation (Nora's lesion) indicate that it is a tumour disease. III: The candidate oncogenes COAS1-3 were amplified in 56 % of 48 BSTTs analyzed. Medium and high-level amplification was primarily seen among lipomatous tumors, where the extra copies were localized preferentially in ring and giant marker chromosomes, often together with amplified MDM2. IV: A new variant type of structural aberration was described in an atypical lipomatous tumor. Intermixed sequences from chromosomes 8 and 12 resulted in extra copies of MDM2 and HMGA2, including a truncated version of the latter. V: Eight lipomas with rearrangements of chromosome bands 12q14-15 and 5q32-33 were analysed by FISH. Five of the cases had a breakpoint in the 5´ part of the early B-cell factor gene (EBF) located at 5q33. On chromosome 12, the breakpoints clustered to the region of the HMGA2 gene. Two new fusion genes, HMGA2/EBF and EBF/BC058822, were identified. In a case with HMGA2/EBF, two splicing variants, one in frame and the other out of frame, were identified.