- Rebeqa Gunnarsson1,*,
- Larry Mansouri1,
- Anders Isaksson1,
- Hanna Goransson1,
- Nicola Cahill1,
- Mattias Jansson1,
- Markus Rasmussen1,
- Jeanette Lundin2,
- Stefan Norin2,
- Anne Mette Buhl3,
- Karin Ekstrom Smedby2,
- Henrik Hjalgrim4,
- Karin Karlsson5,
- Jesper Jurlander3,
- Christian Geisler3,
- Gunnar Juliusson5 and
- Richard Rosenquist1
- 1 Uppsala University, Sweden;
- 2 Karolinska Institutet, Stockholm, Sweden;
- 3 Rigshospitalet, Copenhagen, Denmark;
- 4 Statens Serum Institut, Copenhagen, Denmark;
- 5 Lund University, Sweden
- ↵* Corresponding author; email:
Background. High-resolution genomic microarrays provides 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 patient samples allows detection of clonal evolution.
Design and Methods. We screened 369 newly diagnosed chronic lymphocytic leukemia patient samples 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 and 70% carried the known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosome 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, whereof 11 concurred with a homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, where the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) IGHV unmutated patients, and in 4/25 (16%) IGHV mutated and treated patients. In contrast, untreated IGHV mutated patients (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 e.g. chromosome 6q, 8p, 9p and 10q developed exclusively in IGHV unmutated patients.
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.
- Received December 23, 2010.
- Accepted April 28, 2011.
- Copyright © 2011, Ferrata Storti Foundation