Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia

作者：Gunnarsson Rebeqa^*; Mansouri Larry; Isaksson Anders; Goransson Hanna; Cahill Nicola; Jansson Mattias; Rasmussen Markus; Lundin Jeanette; Norin Stefan; Buhl Anne Mette; Smedby Karin Ekstrom; Hjalgrim Henrik; Karlsson Karin; Jurlander Jesper; Geisler Christian; Juliusson Gunnar; Rosenquist Richard

来源：Haematologica-The Hematology Journal, 2011, 96(8): 1161-1169.

DOI：10.3324/haematol.2010.039768

• chronic lymphocytic leukemia
• chronic lymphocytic leukemia
• SNP-array
• genomic aberrations
• CNN-LOH
• clonal evolution

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.
Design and 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.

• 出版日期2011-8