Chromosomal Instability Substantiates Poor Prognosis in Patients with Diffuse Large B-cell Lymphoma

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. Clin Cancer Res; 17(24); 7704–11. ©2011 AACR.

[1]  A. Di Leonardo,et al.  Simultaneous Aurora-A/STK15 overexpression and centrosome amplification induce chromosomal instability in tumour cells with a MIN phenotype , 2007, BMC Cancer.

[2]  J. Schellens,et al.  Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  Alexey Khodjakov,et al.  Merotelic Kinetochore Orientation Is a Major Mechanism of Aneuploidy in Mitotic Mammalian Tissue Cells , 2001, The Journal of cell biology.

[4]  S. Flamant,et al.  JC human polyomavirus is associated to chromosomal instability in peripheral blood lymphocytes of Hodgkin's lymphoma patients and poor clinical outcome. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  Bert Vogelstein,et al.  Mutations of mitotic checkpoint genes in human cancers , 1998, Nature.

[6]  L. Insabato,et al.  Chromosomal instability in gastric mucosa-associated lymphoid tissue lymphomas: a fluorescent in situ hybridization study using a tissue microarray approach. , 2008, Human pathology.

[7]  A. Cheung,et al.  Telomere dysfunction, genome instability and cancer. , 2008, Frontiers in bioscience : a journal and virtual library.

[8]  N. Kakazu,et al.  Chromosome 7 abnormalities in acute megakaryoblastic leukemia associated with Down syndrome. , 2005, Cancer genetics and cytogenetics.

[9]  B. Johansson,et al.  Trisomy 8 as the sole chromosomal aberration in acute myeloid leukemia and myelodysplastic syndromes. , 2007, Pathologie-biologie.

[10]  Nicolai J. Birkbak,et al.  Chromosomal instability confers intrinsic multidrug resistance. , 2011, Cancer research.

[11]  M. Fiegl,et al.  Diffuse Large B-Cell Lymphoma with Overexpression of Cyclin E Substantiates Poor Standard Treatment Response and Inferior Outcome , 2006, Clinical Cancer Research.

[12]  William T. Silkworth,et al.  Multipolar Spindle Pole Coalescence Is a Major Source of Kinetochore Mis-Attachment and Chromosome Mis-Segregation in Cancer Cells , 2009, PloS one.

[13]  Samuel F. Bakhoum,et al.  Genome stability is ensured by temporal control of kinetochore-microtubule dynamics , 2008, Nature Cell Biology.

[14]  Nicholas D. Socci,et al.  Mad2-induced chromosome instability leads to lung tumor relapse after oncogene withdrawal , 2010, Nature.

[15]  David Pellman,et al.  A Mechanism Linking Extra Centrosomes to Chromosomal Instability , 2009, Nature.

[16]  D. Compton,et al.  Mechanisms of Chromosomal Instability , 2010, Current Biology.

[17]  Z. Szallasi,et al.  Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[18]  C. Swanton,et al.  Chromosomal Instability, Colorectal Cancer and Taxane Resistance , 2006, Cell cycle.

[19]  D. Baker,et al.  Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. , 2009, Cancer cell.

[20]  Karl J. Dykema,et al.  Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations , 2007, Proceedings of the National Academy of Sciences.

[21]  Cristina Montagna,et al.  Aneuploidy acts both oncogenically and as a tumor suppressor. , 2007, Cancer cell.

[22]  W. Lingle,et al.  Deregulation of the centrosome cycle and the origin of chromosomal instability in cancer. , 2005, Advances in experimental medicine and biology.

[23]  Rocio Sotillo,et al.  Mitotic chromosomal instability and cancer: mouse modelling of the human disease , 2010, Nature Reviews Cancer.

[24]  F. Mugneret,et al.  Anomalies chromosomiques dans les leucémies aiguës myéloïdes , 2003 .

[25]  M. Pino,et al.  The chromosomal instability pathway in colon cancer. , 2010, Gastroenterology.

[26]  L. Mazzucchelli,et al.  Chromosome instability and translocation t(11;18) in primary gastric marginal zone B‐cell lymphoma of MALT‐type , 2007, Hematological oncology.

[27]  S. Jacquemont,et al.  High risk of malignancy in mosaic variegated aneuploidy syndrome. , 2002, American journal of medical genetics.

[28]  R. Houlston,et al.  Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis , 2008, Gut.

[29]  Z. Szallasi,et al.  A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers , 2006, Nature Genetics.

[30]  J. Ptak,et al.  Three classes of genes mutated in colorectal cancers with chromosomal instability. , 2004, Cancer research.

[31]  D. Compton,et al.  Deviant Kinetochore Microtubule Dynamics Underlie Chromosomal Instability , 2009, Current Biology.

[32]  Yuri Fedoriw,et al.  Genetic tests to evaluate prognosis and predict therapeutic response in acute myeloid leukemia. , 2010, The Journal of molecular diagnostics : JMD.

[33]  D. Soler,et al.  Different outcomes of telomere-dependent anaphase bridges. , 2010, Biochemical Society transactions.

[34]  F. Kittrell,et al.  Overexpression of Separase induces aneuploidy and mammary tumorigenesis , 2008, Proceedings of the National Academy of Sciences.

[35]  R. Medema,et al.  Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells , 2009, Proceedings of the National Academy of Sciences.

[36]  R. Benezra,et al.  Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition. , 2011, Cancer cell.

[37]  K. Kinzler,et al.  Genetic instability in colorectal cancers , 1997, Nature.

[38]  Duane A. Compton,et al.  Examining the link between chromosomal instability and aneuploidy in human cells , 2008, The Journal of cell biology.

[39]  Zoltan Szallasi,et al.  Paradoxical relationship between chromosomal instability and survival outcome in cancer. , 2011, Cancer research.

[40]  S. Sleijfer,et al.  Patterns and incidence of chromosomal instability and their prognostic relevance in breast cancer subtypes , 2011, Breast Cancer Research and Treatment.

[41]  M. Horne,et al.  Chromosomal instability and supernumerary centrosomes represent precursor defects in a mouse model of T-cell lymphoma. , 2007, Cancer research.

[42]  F. Sera,et al.  Evaluation of radiation-induced chromosome instability in subjects with a family history of gastric cancer , 2009, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[43]  Emili Montserrat,et al.  A predictive model for aggressive non-Hodgkin's lymphoma. , 1993, The New England journal of medicine.

[44]  H. Müller-Hermelink,et al.  Centrosome aberrations as a possible mechanism for chromosomal instability in non-Hodgkin's lymphoma , 2003, Leukemia.

[45]  D. Compton,et al.  CLASP1, astrin and Kif2b form a molecular switch that regulates kinetochore‐microtubule dynamics to promote mitotic progression and fidelity , 2010, The EMBO journal.

[46]  K. Kinzler,et al.  Genetic instabilities in human cancers , 1998, Nature.

[47]  N. Rahman,et al.  Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B , 2004, Nature Genetics.

[48]  D. Cimini.  Merotelic kinetochore orientation, aneuploidy, and cancer. , 2008, Biochimica et biophysica acta.

[49]  Dominik Wodarz,et al.  The optimal rate of chromosome loss for the inactivation of tumor suppressor genes in cancer. , 2004, Proceedings of the National Academy of Sciences of the United States of America.