Department of Biochemistry; The Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755, USA.
Clin Cancer Res. 2011 Dec 15;17(24):7704-11. doi: 10.1158/1078-0432.CCR-11-2049.
The specific role of chromosomal instability (CIN) in tumorigenesis has been a matter of conjecture. In part, this is due to the challenge of directly observing chromosome mis-segregation events as well as the inability to distinguish the role of CIN, which consists of increased rates of chromosome mis-segregation, from that of aneuploidy, which is a state of nondiploid chromosome number.
Here, we examine the contribution of CIN to the prognosis of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) by directly surveying tumor cells, fixed while undergoing anaphase, for evidence of chromosome mis-segregation. Hematoxylin and eosin-stained samples from a cohort of 54 patients were used to examine the relationship between frequencies of chromosome mis-segregation and patient prognosis, overall survival, and response to treatment.
We show that a two-fold increase in the frequency of chromosome mis-segregation led to a 24% decrease in overall survival and 48% decrease in relapse-free survival after treatment. The HR of death in patients with increased chromosome mis-segregation was 2.31 and these patients were more likely to present with higher tumor stage, exhibit tumor bone marrow involvement, and receive a higher International Prognostic Index score.
Increased rates of chromosome mis-segregation in DLBCL substantiate inferior outcome and poor prognosis. This is likely due to increased heterogeneity of tumor cells leading to a larger predilection for adaptation in response to external pressures such as metastasis and drug treatments. We propose that targeting CIN would yield superior prognosis and improved response to chemotherapeutic drugs.
染色体不稳定性（CIN）在肿瘤发生中的具体作用一直是人们猜测的对象。部分原因是由于直接观察染色体错误分离事件的挑战，以及无法区分 CIN 的作用，CIN 包括染色体错误分离率的增加，以及非整倍体的作用，非整倍体是染色体数目非整倍体的状态。
在这里，我们通过直接观察处于后期的肿瘤细胞中是否存在染色体错误分离的证据，来检查 CIN 对诊断为弥漫性大 B 细胞淋巴瘤（DLBCL）的患者预后的贡献。使用来自 54 名患者队列的苏木精和伊红染色样本，检查染色体错误分离的频率与患者预后、总生存率和对治疗的反应之间的关系。
我们表明，染色体错误分离频率增加一倍导致总生存率降低 24%，治疗后无复发生存率降低 48%。染色体错误分离增加的患者死亡风险比为 2.31，这些患者更有可能出现更高的肿瘤分期、表现出肿瘤骨髓受累，并且接受更高的国际预后指数评分。
在 DLBCL 中，染色体错误分离率的增加证实了不良结局和预后不良。这可能是由于肿瘤细胞的异质性增加，导致在应对转移和药物治疗等外部压力时更容易适应。我们提出，靶向 CIN 将产生更好的预后，并提高对化疗药物的反应。
