title: Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia.
abstract: BACKGROUND
  High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution.
  
  
  METHODS
  We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years.
  
  
  RESULTS
  At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV.
  
  
  CONCLUSIONS
  Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. rebeqa.gunnarsson@igp.uu.se
authors.forename: Rebeqa
authors.initials: R
authors.lastname: Gunnarsson
authors.forename: Larry
authors.initials: L
authors.lastname: Mansouri
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.forename: Hanna
authors.initials: H
authors.lastname: Göransson
authors.forename: Nicola
authors.initials: N
authors.lastname: Cahill
authors.forename: Mattias
authors.initials: M
authors.lastname: Jansson
authors.forename: Markus
authors.initials: M
authors.lastname: Rasmussen
authors.forename: Jeanette
authors.initials: J
authors.lastname: Lundin
authors.forename: Stefan
authors.initials: S
authors.lastname: Norin
authors.forename: Anne Mette
authors.initials: AM
authors.lastname: Buhl
authors.forename: Karin Ekström
authors.initials: KE
authors.lastname: Smedby
authors.forename: Henrik
authors.initials: H
authors.lastname: Hjalgrim
authors.forename: Karin
authors.initials: K
authors.lastname: Karlsson
authors.forename: Jesper
authors.initials: J
authors.lastname: Jurlander
authors.forename: Christian
authors.initials: C
authors.lastname: Geisler
authors.forename: Gunnar
authors.initials: G
authors.lastname: Juliusson
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002869:Chromosome Aberrations; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D005500:Follow-Up Studies; D015894:Genome, Human; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D019656:Loss of Heterozygosity / Q000235:genetics; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D016019:Survival Analysis; D055815:Young Adult