Gliomas are the most common primary brain tumours in the adult central nervous system, with glioblastoma multiforme (GBM) being the most aggressive type among them [1–3]. GBMs are characterized by extensive inter-and intratumour heterogeneity manifested in morphology, gene expression and genetic abnormalities [4–7]. Several studies have demonstrated that cytogenetically related or unrelated clones coexist in different regions within the same GBM specimen [7–10] and this cytogenetic heterogeneity could correspond to phenotypically diverse cell populations. The cytogenetic heterogeneity is typically concurrent with a high degree of cytogenetic complexity, including both numerical and structural chromosome aberrations. The most common recurrent changes that have been reported in GBM include gain of chromosome 7, losses of 9p sequences and chromosome 10, and gene amplification, primarily of the epidermal growth factor receptor (EGFR) gene [11,12]. Among high-grade glioma, one set of the chromosome changes seen in a tumour is typically common to the vast majority of the tumour cells, whereas other sets of chromosome rearrangements are restricted to subpopulations of tumour cells . However, several cytogenetic studies have shown that GBMs are monoclonal in origin [13–15]. Recently, a small subpopulation of CD133+ GBM cells have been identified as GBM stem cells [4–6,16,17]. Phenotypically, these cells express the stem cell marker CD133 and they functionally posses the ability to regenerate CD133+ cells and to initiate tumour growth when grafted into the central nervous systems of animals. Taken together, this indicates that cytogenetically and phenotypically diverse subclones are generated during tumour development, possibly resulting from a combination of selection and loss of genetic stability .
One mechanism behind genetic instability and karyotypic diversity in tumours is abnormal chromosome segregation at cell division . The most common type of unbalanced chromatid segregation so far identified consists of failed chromatid segregation at anaphase due to the formation of a chromatin bridge. Such anaphase bridges may break at later stages in cell division and the broken ends can reunite into complex structural chromosome changes in the daughter cells [19,20]. The formation of anaphase bridges has been strongly associated with shortening of telomeric repeat sequences, leading to disruption of the telosomic nucleoprotein complex normally protecting the integrity of chromosome ends . Nonhomologous end-joining of unprotected chromosome ends may, in turn, lead to formation of functionally dicentric chromosomes that can form bridges when the two centromeres in each chromatid are pulled in different directions at anaphase. This mechanism has been shown to contribute to cytogenetic intratumour heterogeneity in cancers of the colon , breast , and several other malignancies. It is not known whether similar processes are active in tumours of the central nervous system. Moreover, it has been little explored to what degree the genomic instability and cytogenetic diversity found in primary tumours are retained in brain tumour xenograft models. This is of interest as hetero- and orthotopic xenografts are often used to study brain tumour biology and response to candidate therapeutic agents [24–29].
In the present study we have attempted to explore these issues by analyses of cytogenetic heterogeneity, chromatid segregation pattern, telomere status, and phenotypic features in primary brain tumours and serial tumour xenografts.