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Genetic intratumour heterogeneity in high-grade brain tumours is associated with telomere-dependent mitotic instability.

Karlsson, Christine LU ; Rebetz, Johan LU ; Stewénius, Ylva LU ; Persson, Annette LU ; Englund, Elisabet LU ; Mandahl, Nils LU ; Mertens, Fredrik LU ; Salford, Leif LU ; Widegren, Bengt LU and Fan, Xiaolong LU , et al. (2007) In Neuropathology & Applied Neurobiology 33(4). p.440-454
Abstract
Glioblastoma multiforme (GBM) and other high-grade brain tumours are typically characterized by complex chromosome abnormalities and extensive intratumour cytogenetic heterogeneity. The mechanisms behind this diversity have been little explored. In this study, we analysed the pattern of chromosome segregation at mitosis in 20 brain tumours. We found an abnormal segregation of chromatids at mitosis through anaphase bridging (10-25% of anaphase cells) in all 10 GBMs. Anaphase bridging was also found in two medulloblastomas (7-15%), one anaplastic astrocytoma (17%) and one oligodendroglioma (6%). These tumours showed a relatively high degree of cytogenetic complexity and heterogeneity. In contrast, cell division abnormalities were not found... (More)
Glioblastoma multiforme (GBM) and other high-grade brain tumours are typically characterized by complex chromosome abnormalities and extensive intratumour cytogenetic heterogeneity. The mechanisms behind this diversity have been little explored. In this study, we analysed the pattern of chromosome segregation at mitosis in 20 brain tumours. We found an abnormal segregation of chromatids at mitosis through anaphase bridging (10-25% of anaphase cells) in all 10 GBMs. Anaphase bridging was also found in two medulloblastomas (7-15%), one anaplastic astrocytoma (17%) and one oligodendroglioma (6%). These tumours showed a relatively high degree of cytogenetic complexity and heterogeneity. In contrast, cell division abnormalities were not found in low-grade brain tumours with less complex karyotypes, including two pilocytic astrocytomas and two ependymomas. Further analysis of two GBMs by fluorescence in situ hybridization with telomeric repeat probes revealed excessive shortening of TTAGGG repeats, indicating dysfunctional protection of chromosome ends. In xenografts established from these GBMs, there was a gradual reduction in cytogenetic heterogeneity through successive passages as the proportion of abnormally short telomeres was reduced and the frequency of anaphase bridges decreased from >25% to 0. However, bridging could be reintroduced in late-passage xenograft cells by pharmacological induction of telomere shortening, using a small-molecule telomerase inhibitor. Telomere-dependent abnormal segregation of chromosomes at mitosis is thus a common phenomenon in high-grade brain tumours and may be one important factor behind cytogenetic intratumour diversity in GBM. (Less)
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Neuropathology & Applied Neurobiology
volume
33
issue
4
pages
440 - 454
publisher
Wiley-Blackwell
external identifiers
  • wos:000247818800007
  • scopus:34447125088
ISSN
1365-2990
DOI
10.1111/j.1365-2990.2007.00832.x
language
English
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yes
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86516d73-0fb3-4a7e-a9d4-ea91290cb6ee (old id 632447)
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2008-08-19 09:16:31
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@article{86516d73-0fb3-4a7e-a9d4-ea91290cb6ee,
  abstract     = {Glioblastoma multiforme (GBM) and other high-grade brain tumours are typically characterized by complex chromosome abnormalities and extensive intratumour cytogenetic heterogeneity. The mechanisms behind this diversity have been little explored. In this study, we analysed the pattern of chromosome segregation at mitosis in 20 brain tumours. We found an abnormal segregation of chromatids at mitosis through anaphase bridging (10-25% of anaphase cells) in all 10 GBMs. Anaphase bridging was also found in two medulloblastomas (7-15%), one anaplastic astrocytoma (17%) and one oligodendroglioma (6%). These tumours showed a relatively high degree of cytogenetic complexity and heterogeneity. In contrast, cell division abnormalities were not found in low-grade brain tumours with less complex karyotypes, including two pilocytic astrocytomas and two ependymomas. Further analysis of two GBMs by fluorescence in situ hybridization with telomeric repeat probes revealed excessive shortening of TTAGGG repeats, indicating dysfunctional protection of chromosome ends. In xenografts established from these GBMs, there was a gradual reduction in cytogenetic heterogeneity through successive passages as the proportion of abnormally short telomeres was reduced and the frequency of anaphase bridges decreased from >25% to 0. However, bridging could be reintroduced in late-passage xenograft cells by pharmacological induction of telomere shortening, using a small-molecule telomerase inhibitor. Telomere-dependent abnormal segregation of chromosomes at mitosis is thus a common phenomenon in high-grade brain tumours and may be one important factor behind cytogenetic intratumour diversity in GBM.},
  author       = {Karlsson, Christine and Rebetz, Johan and Stewénius, Ylva and Persson, Annette and Englund, Elisabet and Mandahl, Nils and Mertens, Fredrik and Salford, Leif and Widegren, Bengt and Fan, Xiaolong and Gisselsson Nord, David},
  issn         = {1365-2990},
  language     = {eng},
  number       = {4},
  pages        = {440--454},
  publisher    = {Wiley-Blackwell},
  series       = {Neuropathology & Applied Neurobiology},
  title        = {Genetic intratumour heterogeneity in high-grade brain tumours is associated with telomere-dependent mitotic instability.},
  url          = {http://dx.doi.org/10.1111/j.1365-2990.2007.00832.x},
  volume       = {33},
  year         = {2007},
}