title: Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia.
abstract: Chronic lymphocytic leukemia (CLL) has a variable clinical course. Presence of specific genomic aberrations has been shown to impact survival outcomes and can help categorize CLL into clinically distinct subtypes. We studied 178 CLL patients enrolled in a prospective study at the University of Michigan, of whom 139 and 39 were previously untreated and previously treated, respectively. We obtained unbiased, high-density, genome-wide measurements of subchromosomal copy number changes in highly purified DNA from sorted CD19(+) cells and buccal cells using the Affymetrix 50kXbaI SNP array platform (Santa Clara, CA). Genomic complexity scores were derived and correlated with the surrogate clinical end points time to first therapy (TTFT) and time to subsequent therapy (TTST): measures of disease aggressiveness and/or therapy efficaciousness. In univariate analysis, progressively increasing complexity scores in previously untreated CLL patients identified patients with short TTFT at high significance levels. Similarly, TTST was significantly shorter in pretreated patients with high as opposed to low genomic complexity. In multivariate analysis, genomic complexity emerged as an independent risk factor for short TTFT and TTST. Finally, algorithmic subchromosomal complexity determination was developed, facilitating automation and future routine clinical application of CLL whole-genome analysis.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109-0936, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kujawski
authors.forename: Peter
authors.initials: P
authors.lastname: Ouillette
authors.forename: Harry
authors.initials: H
authors.lastname: Erba
authors.forename: Chris
authors.initials: C
authors.lastname: Saddler
authors.forename: Andrzej
authors.initials: A
authors.lastname: Jakubowiak
authors.forename: Mark
authors.initials: M
authors.lastname: Kaminski
authors.forename: Kerby
authors.initials: K
authors.lastname: Shedden
authors.forename: Sami N
authors.initials: SN
authors.lastname: Malek
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D016158:Genes, p53; D023281:Genomics / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D013997:Time Factors; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D007143:Immunoglobulin Heavy Chains; D008562:Membrane Glycoproteins; D051746:ZAP-70 Protein-Tyrosine Kinase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1