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Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers
Yuesheng Jin1, Ylva Stewénius, David Lindgren
1Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
Summary
Chromosomal instability in urothelial cancer arises from errors in chromosome segregation. High rates of these mitotic errors predict poor survival, yet inhibiting telomerase to increase errors reduced tumor cell growth.
Area of Science:
- Oncology
- Genetics
- Cell Biology
Background:
- Chromosomal instability (CIN) is implicated in urothelial cancer (UC) pathogenesis.
- Mitotic segregation is a key process influencing genomic integrity.
Purpose of the Study:
- To investigate the contribution of mitotic segregation disturbances to CIN in UC.
- To determine the impact of these processes on disease progression and tumor cell growth.
Main Methods:
- Developed molecular cytogenetic methods to classify mitotic segregation abnormalities in UC cell lines.
- Scored mitotic instabilities in 52 UC patient biopsies and correlated with disease outcome.
- Assessed the effect of a telomerase inhibitor on mitotic stability and proliferation in UC cells in vitro.
Main Results:
- Identified three distinct segregation abnormalities: telomere dysfunction, sister chromatid nondisjunction, and supernumerary centrosomes.
- Mitotic errors were present in preinvasive tumors, and high rates predicted poor survival.
- Telomerase inhibition-induced segregation abnormalities reduced UC cell proliferation and survival.
Conclusions:
- Distinct chromosome segregation errors contribute to CIN in UC.
- The rate of mitotic errors significantly impacts the clinical course of urothelial cancer.
- Endogenous control of these processes is crucial for efficient tumor cell proliferation.
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