title: Chromosomal instability substantiates poor prognosis in patients with diffuse large B-cell lymphoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Biochemistry; The Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755, USA. samuel.bakhoum@dartmouth.edu
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Bakhoum
authors.forename: Olga V
authors.initials: OV
authors.lastname: Danilova
authors.forename: Prabhjot
authors.initials: P
authors.lastname: Kaur
authors.forename: Norman B
authors.initials: NB
authors.lastname: Levy
authors.forename: Duane A
authors.initials: DA
authors.lastname: Compton
mesh_terms: D000368:Aged; D000705:Anaphase / Q000235:genetics*; D000782:Aneuploidy; D016009:Chi-Square Distribution; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D013997:Time Factors