Defective chromosome segregation and telomere dysfunction in aggressive Wilms' tumors.
OBJECTIVE
In many childhood neoplasms, prognostic subgroups have been defined based on specific chromosome changes. In Wilms' tumor (WT), such subclassification has been hampered by the diverse and relatively unspecific pattern of chromosomal imbalances present in these tumors. Unspecific patterns of cytogenetic imbalances in tumors are often caused by mitotic segregation errors due to short dysfunctional telomeres. As an alternative to cytogenetic classification, we therefore have evaluated whether the rate of telomere-dependent chromosomal instability could influence the clinical course in WT patients.


METHODS
Telomere function and mitotic segregation errors were assessed in 12 cultured tumors and in tumor tissue sections from 41 WT patients.


RESULTS
Abnormal telomere shortening was found in cultured cells and in tissue sections from highly aggressive tumors. In vitro, dysfunctional telomeres were associated to specific cell division abnormalities, including anaphase bridges and multipolar mitoses. Assessment of mitotic figures in tissue sections revealed that anaphase bridges and multipolar mitoses were predominantly, but not exclusively, present in high-risk tumors and were predictors of poor event-free and overall survival.


CONCLUSIONS
Telomere-dependent mitotic instability is present in a subgroup of WT, predominantly consisting of high-risk tumors.
Stewénius
Ylva
Y
Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. ylva.stewenius@med.lu.se
Jin
Yuesheng
Y
Øra
Ingrid
I
de Kraker
Jan
J
Bras
Johannes
J
Frigyesi
Attila
A
Alumets
Jan
J
Sandstedt
Bengt
B
Meeker
Alan K
AK
Gisselsson
David
D
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D020090:Chromosome Segregation; D005260:Female; D006801:Humans; D007223:Infant; D007680:Kidney Neoplasms / Q000401:mortality / Q000473:pathology*; D008297:Male; D008938:Mitosis; D011379:Prognosis; D016615:Telomere / Q000648:ultrastructure*; D009396:Wilms Tumor / Q000401:mortality / Q000473:pathology*