Abstract 4600: Examining the selective contribution of chromosomal instability to tumor evolution and prognosis

Abstract

Abstract 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 dynamic whole-chromosome mis-segregation events as well as the lack of firm understanding of the mechanisms that lead to CIN in cancer. These shortcomings have long prevented the ability to distinguish the role of CIN, which consists of increased rates of chromosome mis-segregation, from that of aneuploidy, which is a state of non-diploid chromosome number. To overcome these limitations, we use human-derived cancer cell lines to understand the biological basis of chromosome mis-segregation. We then extend these findings to tumor samples from patients diagnosed with Diffuse Large B-Cell Lymphoma to examine the selective contribution of CIN to tumor prognosis and evolution. We show that, in human cancer cell lines, chromosome mis-segregation occurs primarily as a result from defective microtubule dynamics, which prevent the correction of erroneous attachments of microtubules to chromosomes during mitosis. These attachment errors lead to the formation of lagging chromosomes and chromatin bridges during anaphase. Strikingly, restoring normal microtubule dynamics significantly decreases chromosome mis-segregation frequencies and suppresses CIN. We then use lagging chromosomes and chromatin bridges as morphological features to examine the selective contribution of CIN to tumor prognosis. Hematoxylin and Eosin-stained samples from a cohort of 54 patients diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) are 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 leads to a 24% decrease in overall survival and 48% decrease in relapse-free survival after treatment. The hazard ratio (HR) of death in patients with increased chromosome mis-segregation is 2.31 and these patients are more likely to present with higher tumor stage, exhibit tumor bone marrow involvement, and receive a higher International Prognostic Index (IPI) score. In summary, this work demonstrates that CIN primarily arises due to defects in the attachments of microtubule to chromosomes. Furthermore, 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 improved prognosis and enhanced response to chemotherapeutic drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4600. doi:1538-7445.AM2012-4600