Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers.
OBJECTIVE
Chromosomal instability (CIN) is believed to have an important role in the pathogenesis of urothelial cancer (UC). The aim of this study was to evaluate whether disturbances of mitotic segregation contribute to CIN in UC, if these processes have any effect on the course of disease, and how deregulation of these mechanisms affects tumor cell growth.


METHODS
We developed molecular cytogenetic methods to classify mitotic segregation abnormalities in a panel of UC cell lines. Mitotic instabilities were then scored in biopsies from 52 UC patients and compared with the outcome of tumor disease. Finally, UC cells were exposed in vitro to a telomerase inhibitor to assess how this affects mitotic stability and cell proliferation.


RESULTS
Three distinct chromosome segregation abnormalities were identified: (a) telomere dysfunction, which triggers structural rearrangements and loss of chromosomes through anaphase bridging; (b) sister chromatid nondisjunction, which generates discrete chromosomal copy number variations; and (c) supernumerary centrosomes, which cause dramatic shifts in chromosome copy number through multipolar cell division. Chromosome segregation errors were already present in preinvasive tumors and a high rate mitotic instability was an independent predictor of poor survival. However, induction of even higher levels of the same segregation abnormalities in UC cells by telomerase inhibition in vitro led to reduced tumor cell proliferation and clonogenic survival.


CONCLUSIONS
Several distinct chromosome segregation errors contribute to CIN in UC, and the rate of such mitotic errors has a significant effect on the clinical course. Efficient tumor cell proliferation may depend on the tight endogenous control of these processes.
Jin
Yuesheng
Y
Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
Stewénius
Ylva
Y
Lindgren
David
D
Frigyesi
Attila
A
Calcagnile
Olga
O
Jonson
Tord
T
Edqvist
Anna
A
Larsson
Nina
N
Lundberg
Lena Maria
LM
Chebil
Gunilla
G
Liedberg
Fredrik
F
Gudjonsson
Sigurdur
S
Månsson
Wiking
W
Höglund
Mattias
M
Gisselsson
David
D
D000368:Aged; D000705:Anaphase; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D020090:Chromosome Segregation / Q000235:genetics*; D006801:Humans; D008938:Mitosis; D009361:Neoplasm Invasiveness; D012854:Sister Chromatid Exchange; D016019:Survival Analysis; D016615:Telomere / Q000737:chemistry; D014178:Translocation, Genetic; D014571:Urologic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D019459:Urothelium / Q000473:pathology