Telomere-mediated mitotic disturbances in immortalized ovarian epithelial cells reproduce chromosomal losses and breakpoints from ovarian carcinoma.
Ovarian carcinomas (OCs) often exhibit highly complex cytogenetic changes. Abnormal chromosome segregation at mitosis is one potential mechanism for genomic rearrangements in tumors. In this study, OCs were demonstrated to have dysfunctional short telomeres, anaphase bridging, and multipolar mitoses with supernumerary centrosomes. When normal human ovarian surface epithelial (HOSE) cells were transfected with human papilloma virus 16 e6/e7 genes and subsequently driven into telomere crisis, the same set of mitotic disturbances occurred in a distinct sequence, initiated by telomere dysfunction, followed by anaphase bridging, and then supernumerary centrosomes and multipolar mitoses. The anaphase bridges resolved either by kinetochore-spindle detachment, corresponding to whole-chromosome losses in the HOSE karyotypes, or by extensive fragmentation of intercentromeric DNA sequences, corresponding to a high frequency of pericentromeric rearrangements. At later passages, the high degree of instability at telomere crisis was moderated by telomerase expression and centrosome coalescence, ultimately leading to a level of mitotic instability that was highly similar to that in OC cell lines and to complex karyotypes that were similar to those observed in high-grade OCs. This suggests that a significant proportion of the structural chromosome changes and genomic losses in OC are caused by a specific sequence of mitotic disturbances triggered by telomere crisis. That the model did not produce any of the whole-chromosome gains observed in OC indicates that these changes develop through a different mechanism.
Gisselsson
David
D
Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China. david.gisselsson@klingen.lu.se
Lv
Mei
M
Tsao
Sai-Wha
SW
Man
Cornelia
C
Jin
Charlotte
C
Höglund
Mattias
M
Kwong
Yok Lam
YL
Jin
Yuesheng
Y
D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002877:Chromosomes, Human / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007621:Karyotyping; D008938:Mitosis / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D016615:Telomere / Q000235:genetics* / Q000648:ultrastructure