Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia - PubMed (original) (raw)

doi: 10.3324/haematol.2010.039768. Epub 2011 May 5.

Larry Mansouri, Anders Isaksson, Hanna Göransson, Nicola Cahill, Mattias Jansson, Markus Rasmussen, Jeanette Lundin, Stefan Norin, Anne Mette Buhl, Karin Ekström Smedby, Henrik Hjalgrim, Karin Karlsson, Jesper Jurlander, Christian Geisler, Gunnar Juliusson, Richard Rosenquist

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

Rebeqa Gunnarsson et al. Haematologica. 2011 Aug.

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.

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.

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Figures

Figure 1.

Figure 1.

Genomic map of homozygous and heterozygous deletion 13q. (A) Chromosomal bands and location in Mbp, (B) genes and (C) a condensed view of the homozygous (light gray) and heterozygous (dark gray) deletions of the enlarged sub-region of deletion at 13q14.2–14.3. The single nucleotide polymorphisms defining the minimally deleted region (MDR) were rs706612 (49608579–49608580 bp) and rs1359612 (49612082-49612082 bp) for the centromeric breakpoint and rs1750567 (49635023–49635024 bp) and rs1798968 (49635869–49635870 bp) for the telomeric breakpoint.

Figure 2.

Figure 2.

Survival and time to treatment according to known recurrent aberrations and deletion 13q size (Kaplan-Meier plots). (A) Patients with del(17p) had the worst outcome, whereas del(11q) and trisomy 12 indicated similar intermediate survival. Patients with no recurrent aberration and patients with del(13q) showed similar good overall survival (P<0.0001). (B) Patients with poor-prognostic markers had a shorter time to treatment than patients with del(13q) and no recurrent aberration (_P_<0001). (C-D) Receiver operating characteristics (ROC) curve analysis and overall survival or time to treatment was applied in order to identify the optimal size cut-off for del(13q). Patients with larger del(13q) (>1.25 Mbp) had an inferior prognosis in terms of overall survival (C) (_P_=0.016), and time to treatment (D) (P<0.01).

Figure 3.

Figure 3.

An increased genomic complexity predicts a worse survival and shorter time to treatment (Kaplan-Meier plots). Overall survival of patients was investigated according to the degree of genomic complexity, which showed (A) an inferior survival (P<0.0001) and (B) shorter time to treatment (P<0.0001) for patients carrying an increasing number of copy number aberrations larger than 5 Mbp.

Figure 4.

Figure 4.

CLL patients with clonal evolution. (A-B) Examples of clonal evolution in two CLL patients for whom the first sample at diagnosis (upper panel) is compared to the follow-up sample in the lower panel of each figure. (A) SCAN 182 (IGHV unmutated and treated) had a normal copy-number of chromosome 10 at diagnosis, and developed a loss of the q-arm in the follow-up sample. (B) SCAN 75 (Binet stage A, IGHV unmutated) had no aberrations at diagnosis but showed a complex genome with deletions on 6q, 8p, 13q, 17p, 18p and a gain on 8q at follow-up after two lines of treatment with alkylating agents.

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