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Osteosarcoma (OS) is characterized by chromosomal instability and high copy number gene amplification. The breakage–fusion–bridge (BFB) cycle is a well-established mechanism of genome instability in tumors and in vitro models used to study the origins of complex chromosomal rearrangements and cancer genome amplification. To determine whether the BFB cycle could be increasing the de novo rate of formation of cytogenetic aberrations in OS, the frequency of anaphase bridge configurations and dicentric chromosomes in four OS cell lines was quantified. An increased level of anaphase bridges and dicentrics was observed in all the OS cell lines. There was also a strong association between the frequencies of anaphase bridges, dicentrics, centrosomal anomalies, and multipolar mitotic figures in all the OS cell lines, indicating a possible link in the mechanisms that led to the structural and numerical instabilities observed in OS. In summary, this study has provided strong support for the role of the BFB cycle in generating the extensive structural chromosome aberrations, as well as cell-to-cell cytogenetic variation observed in OS, thus conferring the genetic diversity for OS tumor progression. [ABSTRACT FROM AUTHOR]

Mechanisms underlying prostate cancer (CaP) initiation and progression are poorly understood. A chromosomal instability mechanism leading to the generation of numerical and structural chromosomal changes has been implicated in the preneoplastic and neoplastic stages of CaP. Telomere dysfunction is one potential mechanism associated with the onset of such instability. To determine whether there was alteration in telomere length and chromosome number, 15 paraffin-embedded prostatectomy specimens were investigated using quantitative peptide nucleic acid (PNA) FISH analysis of representative foci of carcinoma, putative precancerous lesions (high-grade prostatic intraepithelial neoplasia, HPIN) and nondysplastic prostate epithelium. A significant decrease in telomere length was shown in both HPIN and CaP in comparison with normal epithelium. In addition, elevated rates of aneusomy suggested that increased levels of chromosomal aberrations were associated with decreased telomere length. Moreover, multiple foci of HPIN were shown to have a heterogeneous overall reduction of telomere length. This reduction was more evident in the histologic regions of the prostate containing CaP. Such observations lend support to the hypothesis that telomere erosion may be a consistent feature of CaP oncogenesis and may also be associated with the generation of chromosomal instability that characterizes this malignancy.Oncogene (2003) 22, 1978-1987. doi:10.1038/sj.onc.1206227 [ABSTRACT FROM AUTHOR]

Interphase nuclei exhibit a cell type-specific topology of chromatin domains. This topology has been proposed to be established at a specific developmental stage and to be associated, in turn, with cell type-specific gene expression. Using murine, cerebellar Purkinje neurons, we have shown previously that the number and the extent of clustering as well as the spatial, intranuclear distribution of centromeric domains change as a function of postnatal development. Specifically, the redistribution of centromeric domains was determined to be associated temporally with major changes in gene expression. Given that centromeric sequences are not transcribed, we tested the hypothesis that the de novo expression of a specific sequence is similarly associated with a change in its spatial, intranuclear position. In Purkinje neurons, Plcβ3 is expressed de novo between postnatal day 2 and 7. In contrast, the level of expression of Rorα remains constant throughout development, following its initial expression at embryonic day 15. Plcβ3 and Rorα were labeled by fluorescence in situ hybridization within intact nuclei and their intranuclear, spatial positions quantified by confocal microscopy. When analyzed as the distance from the nuclear centroid, the mean fraction of radial distance of Plcβ3 signals changed from 57.3%±2.35 (±SEM) (n=50) at P3 to 37.9%±2.35 (n=50) at P5. In contrast, the mean fraction of the radial distance of Rorα signals did not change during postnatal development, remaining at a mean of 60.1%±2.01(n=208) from the nuclear centroid. While the results do not support a causal relationship between the spatial relocation of Plcβ3 and its de novo expression, their temporal association, as described herein, may be taken to support the hypothesis that its intranuclear, spatial positioning may represent one level of transcriptional control. [ABSTRACT FROM AUTHOR]

Chromatin in interphase nuclei exhibits a topology that is associated with the transcriptional state of cells. We examined the spatial, intranuclear distribution of chromosome 17 and the ERBB-2 ( HER2/neu) sequence thereon, relative to that of DNase-hypersensitive chromatin (DHC), in breast tumour cells exhibiting different levels of expression of ERBB-2. These sequences were specifically associated with the nuclear periphery, within a band of DHC. The remainder of the chromosome 17 mass showed no preferential position within the nucleus. The peripheral placement of ERBB-2 sequences is associated with a specific conformation of chromosome 17. We propose that the conformational organization of chromosome territories might represent a fundamental control mechanism in gene expression. [ABSTRACT FROM AUTHOR]