Abstract
Acute lymphoblastic leukemia is the most common pediatric cancer characterized by a heterogeneous genomic landscape with copy number aberrations occurring at various stages of pathogenesis, disease progression, and treatment resistance. In this study, disease-relevant copy number aberrations were profiled in bone marrow samples of 91 children with B- or T-cell precursor acute lymphoblastic leukemia using digital multiplex ligation-dependent probe amplification (digitalMLPATM). Whole chromosome gains and losses, subchromosomal copy number aberrations, as well as unbalanced alterations conferring intrachromosomal gene fusions were simultaneously identified with results available within 36 hours. Aberrations were observed in 96% of diagnostic patient samples, and increased numbers of copy number aberrations were detected at the time of relapse as compared with diagnosis. Comparative scrutiny of 24 matching diagnostic and relapse samples from 11 patients revealed three different patterns of clonal relationships with (i) one patient displaying identical copy number aberration profiles at diagnosis and relapse, (ii) six patients showing clonal evolution with all lesions detected at diagnosis being present at relapse, and (iii) four patients displaying conserved as well as lost or gained copy number aberrations at the time of relapse, suggestive of the presence of a common ancestral cell compartment giving rise to clinically manifest leukemia at different time points during the disease course. A newly introduced risk classifier combining cytogenetic data with digitalMLPATM-based copy number aberration profiles allowed for the determination of four genetic subgroups of B-cell precursor acute lymphoblastic leukemia with distinct event-free survival rates. DigitalMLPATM provides fast, robust, and highly optimized copy number aberration profiling for the genomic characterization of acute lymphoblastic leukemia samples, facilitates the decipherment of the clonal origin of relapse and provides highly relevant information for clinical prognosis assessment.
Highlights
Acute lymphoblastic leukemia is the most common malignancy in childhood and includes several subtypesDepartment of Pathology, University of Pécs Clinical Centre, Pécs, HungaryDepartment of Molecular Genetics and Diagnostics, National Center of Public Health, Budapest, HungaryDepartment of Paediatrics, University of Pécs Clinical Centre, Pécs, HungaryDepartment of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The NetherlandsComprehensive profiling of disease-relevant copy number aberrations for advanced clinical diagnostics. . .characterized by recurrent genetic alterations [1]
In line with previously published data [13], analysis of a dilution series prepared from the diagnostic sample of patient #51 harboring seven mono- and two biallelic losses on autosomal chromosomes demonstrated that the method efficiently detects clonal copy number aberrations in samples with at least 30% leukemic cell purity (Supplementary Table 3); a cutoff that was exceeded by all samples analyzed in this study
5.4 copy number aberrations were detected per patient (B-cell precursor acute lymphoblastic leukemia: 6.0, T-cell precursor acute lymphoblastic leukemia: 2.6) with a mean of 2.8 subchromosomal aberrations (B-cell precursor acute lymphoblastic leukemia: 2.9, T-cell precursor acute lymphoblastic leukemia: 2.5)
Summary
Acute lymphoblastic leukemia is the most common malignancy in childhood and includes several subtypesComprehensive profiling of disease-relevant copy number aberrations for advanced clinical diagnostics. . .characterized by recurrent genetic alterations [1]. Subchromosomal lesions frequently involve key regulators of cell cycle control, tumor suppression, as well as lymphoid cell development/differentiation [2, 3], and were shown to be associated with clinical outcome leading to the recent introduction of copy number aberration-based risk stratification classifiers (IKZF1plus and UKALL-CNA) in B-cell precursor acute lymphoblastic leukemia [8,9,10]. Individual patients with acute lymphoblastic leukemia harbor a limited number of somatic copy number aberrations as determined by previous molecular array-based and next-generation sequencing studies [2, 11], comprehensive and cost-efficient screening of disease-relevant aberrations requires highly multiplexed, targeted approaches due to the relatively wide repertoire of recurrently altered genomic loci that can potentially be affected. The frequently variable and small size of subchromosomal aberrations hamper the sensitive detection of copy number aberrations by using conventional methods, such as karyotyping, fluorescence in situ hybridization, or off-the-shelf array-based assays [12]
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