Distinct Mitotic Segregation Errors Mediate Chromosomal Instability in Aggressive Urothelial Cancers

Abstract

Purpose: 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. Experimental Design: 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. Conclusion: 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.

Combined Gene Expression and Genomic Profiling Define Two Intrinsic Molecular Subtypes of Urothelial Carcinoma and Gene Signatures for Molecular Grading and Outcome

“…Hence, the results suggest that a major difference between MS1 and MS2 tumors is that the latter are more likely to have passed through a phase of genomic instability, augmented in the presence of TP53 impairment. This is in line with the finding that the presence of aberrant mitoses in pathologic slides of urothelial carcinoma is associated with a poor prognosis (47). The near absence of FGA in MS1 tumors with TP53/MDM2 mutations and the significantly higher number of FGA in MS2 TP53/MDM2wt cases suggests that the critical event separating MS1 tumors from MS2 tumors is a preceding phase of genomic instability and not the impairment of TP53 activity per se.…”

Defective Chromosome Segregation and Telomere Dysfunction in Aggressive Wilms' Tumors

“…Cell culture, harvest, and chromosome preparation for banding and fluorescence in situ hybridization (FISH) were according to standard methods (26). For analysis of chromosome dynamics at mitosis in tissue cultures, cells were harvested without metaphase arrest and stained with H&E. Anaphase cells and metaphase cells were scored in each case with AB and MM as defined by Jin et al (27).…”

Classification of chromosome segregation errors in cancer

“…Furthermore, several recent studies have indicated that a high rate of such errors may be an adverse prognostic marker in several types of tumours (Yamamoto et al 2006;Jin et al 2007;Stewénius et al 2007) and that disturbances of chromosome segregation may be an early event in carcinogenesis (Meeker et al 2004). Hansemann described three types of chromosome segregation errors in tumour tissue sections (Hansemann 1891): anaphase bridges, multipolar mitoses, and asymmetrical bipolar mitoses.…”