Stewénius Ylva, Jin Yuesheng, Øra Ingrid, de Kraker Jan, Bras Johannes, Frigyesi Attila, Alumets Jan, Sandstedt Bengt, Meeker Alan K, Gisselsson David
Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
Clin Cancer Res. 2007 Nov 15;13(22 Pt 1):6593-602. doi: 10.1158/1078-0432.CCR-07-1081.
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.
Telomere function and mitotic segregation errors were assessed in 12 cultured tumors and in tumor tissue sections from 41 WT patients.
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.
Telomere-dependent mitotic instability is present in a subgroup of WT, predominantly consisting of high-risk tumors.
在许多儿童肿瘤中，预后亚组是根据特定的染色体变化来定义的。在肾母细胞瘤（WT）中，这种亚分类受到这些肿瘤中存在的多样且相对不特异的染色体失衡模式的阻碍。肿瘤中细胞遗传学失衡的非特异模式通常是由功能失调的短端粒导致的有丝分裂分离错误引起的。因此，作为细胞遗传学分类的替代方法，我们评估了端粒依赖性染色体不稳定性的速率是否会影响WT患者的临床病程。
在12个培养的肿瘤以及41例WT患者的肿瘤组织切片中评估端粒功能和有丝分裂分离错误。
在培养细胞和高度侵袭性肿瘤的组织切片中发现了异常的端粒缩短。在体外，功能失调的端粒与特定的细胞分裂异常有关，包括后期桥和多极有丝分裂。对组织切片中有丝分裂图像的评估显示，后期桥和多极有丝分裂主要但并非仅存在于高危肿瘤中，并且是无事件生存期和总生存期较差的预测指标。
端粒依赖性有丝分裂不稳定性存在于WT的一个亚组中，主要由高危肿瘤组成。
