Chromosomal Instability and Genomic Amplification in Bone and Soft Tissue Tumours
Abstract: Acquired genetic abnormalities are found in all types of malignant tumours and may contribute to neoplastic processes by altering protein structure or dosage. Many bone and soft tissue tumours (BSTT) are characterised by complex patterns of chromosome changes, including extensive intratumour heterogeneity and amplification of DNA sequences. The results presented in this thesis demonstrate that the cytogenetic heterogeneity in a number of BSTT may, to a considerable extent, be caused by ring and dicentric chromosomes involved in breakage-fusion-bridge (BFB) events, as shown by the strong correlation between sequences present in mitotically unstable chromosomes and anaphase bridges. In borderline/low-malignant tumours with ring chromosomes carrying amplified sequences from chromosome 12, BFB rearrangements are associated with intratumour variability in the organisation of amplified material and abnormalities in centromeric alpha satellite sequences, including neocentromere formation. After the healing of broken ends by telomeric sequences from other chromosomes, rings may transform into giant marker chromosomes, which may occasionally be dicentric and rearrange further. BFB instability is also present in highly malignant tumours exhibiting a complex, unspecific, and heterogeneous pattern of chromosome aberrations. These neoplasms typically show unstable dicentric chromosomes and a general destabilisation of the chromosome complement. Tumour cells with BFB instability exhibit a decreased elimination rate of mitotically unstable chromosomes, which may be partly related to disruption of the normal TP53–dependent DNA damage response. In both BSTT and epithelial tumours, BFB events are associated with specific abnormalities in nuclear shape, indicating that nuclear atypia may serve as an indicator of ongoing genomic reorganisation in neoplastic cell populations.
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