title: Clonal evolution, genomic drivers, and effects of therapy in chronic lymphocytic leukemia.
abstract: OBJECTIVE
  The identification of gene mutations and structural genomic aberrations that are critically involved in chronic lymphocytic leukemia (CLL) pathogenesis is still evolving. One may postulate that genomic driver lesions with effects on CLL cell proliferation, apoptosis thresholds, or chemotherapy resistance should increase in frequency over time when measured sequentially in a large CLL cohort.
  
  
  METHODS
  We sequentially sampled a large well-characterized CLL cohort at a mean of 4 years between samplings and measured acquired copy number aberrations (aCNA) and LOH using single-nucleotide polymorphism (SNP) 6.0 array profiling and the mutational state of TP53, NOTCH1, and SF3B1 using Sanger sequencing. The paired analysis included 156 patients, of whom 114 remained untreated and 42 received intercurrent therapies, predominantly potent chemoimmunotherapy, during the sampling interval.
  
  
  RESULTS
  We identify a strong effect of intercurrent therapies on the frequency of acquisition of aCNAs in CLL. Importantly, the spectrum of acquired genomic changes was largely similar in patients who did or did not receive intercurrent therapies; therefore, various genomic changes that become part of the dominant clones are often already present in CLL cell populations before therapy. Furthermore, we provide evidence that therapy of CLL with preexisting TP53 mutations results in outgrowth of genomically very complex clones, which dominate at relapse.
  
  
  CONCLUSIONS
  Using complementary technologies directed at the detection of genomic events that are present in substantial proportions of the clinically relevant CLL disease bulk, we capture aspects of genomic evolution in CLL over time, including increases in the frequency of genomic complexity, specific recurrent aCNAs, and TP53 mutations.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Ouillette
authors.forename: Kamlai
authors.initials: K
authors.lastname: Saiya-Cork
authors.forename: Erlene
authors.initials: E
authors.lastname: Seymour
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Kerby
authors.initials: K
authors.lastname: Shedden
authors.forename: Sami N
authors.initials: SN
authors.lastname: Malek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D060965:Clonal Evolution / Q000235:genetics*; D056915:DNA Copy Number Variations; D018450:Disease Progression; D005260:Female; D023281:Genomics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1 / Q000235:genetics; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D016159:Tumor Suppressor Protein p53