Telomere‐mediated mitotic disturbances in immortalized ovarian epithelial cells reproduce chromosomal losses and breakpoints from ovarian carcinoma

Abstract

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.

Distinct Mitotic Segregation Errors Mediate Chromosomal Instability in Aggressive Urothelial Cancers

“…1H). Recent studies have suggested that T-CIN may also result in loss of whole chromosomes (9,28). The morphology of anaphase bridge in our panel of cell lines suggested that this could be the case also in UC because f10% to 20% of mitoses with anaphase bridge showed a complete dislocation of the bridge from one of the anaphase poles (Fig.…”

Cell Cycle Disturbances and Mitotic Catastrophes in HeLa Hep2 Cells following 2.5 to 10 Gy of Ionizing Radiation

“…It has previously been shown that expression of the human papillomavirus E6 and E7 proteins in epithelial cells may trigger abnormal spindle pole formation by an abundant number of centrosomes in parallel with the occurrence of anaphase bridges (24 -26). This centrosome amplification has been shown to appear due to failure in cytokinesis, leading to formation of cells with a 2-fold amount of both chromosomes and centrosomes (26), explaining the relatively high numbers of control cells with abundant numbers of centrosomes observed.…”

“…Anaphase bridges may be generated when broken chromosomes, either induced by irradiation or triggered by abnormal shortening of the telomeres, fuse (21,26). These anaphase bridges usually are resolved by new chromosomal breakages (27).…”

High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis

“…7 Tumors with high rates of anaphase bridging (such as ovarian, head and neck tumors) are characterized by a multimodal distribution of genomic imbalances, consistent with a dramatically increased rate of chromosomal rearrangement. 8,9 Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide, accounting for the highest number of adult malignancies in areas endemic for hepatitis B virus (HBV). Telomere shortening is an early event in multistep hepatocarcinogenesis, occurring in preneoplastic lesions of dysplastic nodules 10,11 and shortened telomeres have been reported to induce chromosomal instability in hepatocytes, especially important in HBV-related hepatocarcinogenesis.…”