Abstract
BackgroundAcute lymphoblastic leukemia (ALL) is not a single uniform disease. It consists of several subgroups with different cytogenetic and molecular genetic aberrations, clinical presentations and outcomes. Banding cytogenetics plays a pivotal role in the detection of recurrent chromosomal rearrangements and is the starting point of genetic analysis in ALL, still. Nowadays, molecular (cyto)genetic tools provide substantially to identify previously non-detectable, so-called cryptic chromosomal aberrations in ALL. However, ALL according to banding cytogenetics with normal karyotype - in short cytogenetically normal ALL (CN-ALL) - represent up to ~50 % of all new diagnosed ALL cases. The overall goal of this study was to identify and characterize the rate of cryptic alterations in CN-ALL and to rule out if one single routine approach may be sufficient to detect most of the cryptic alterations present.ResultsSixty-one ALL patients with CN-ALL were introduced in this study. All of them underwent high resolution fluorescence in situ hybridization (FISH) analysis. Also DNA could be extracted from 34 ALL samples. These DNA-samples were studied using a commercially available MLPA (multiplex ligation-dependent probe amplification) probe set directed against 37 loci in hematological malignancies and/or array-comparative genomic hybridization (aCGH). Chromosomal aberrations were detected in 21 of 61 samples (~34 %) applying FISH approaches: structural abnormalities were present in 15 cases and even numerical ones were identified in 6 cases. Applying molecular approaches copy number alterations (CNAs) were detected in 27/34 samples. Overall, 126 CNAs were identified and only 34 of them were detectable by MLPA (~27 %). Loss of CNs was identified in ~80 % while gain of CNs was present in ~20 % of the 126 CNAs. A maximum of 13 aberrations was detected per case; however, only one aberration per case was found in 8 of all in detail studied 34 cases. Of special interest among the detected CNAs are the following new findings: del(15)(q26.1q26.1) including CHD2 gene was found in 20 % of the studied ALL cases, dup(18)(q21.2q21.2) with the DCC gene was present in 9 % of the cases, and the CDK6 gene in 7q21.2 was deleted in 12 % of the here in detail studied ALL cases.ConclusionsIn conclusion, high resolution molecular cytogenetic tools and molecular approaches like MLPA and aCGH need to be combined in a cost-efficient way, to identify disease and progression causing alterations in ALL, as majority of them are cryptic in banding cytogenetic analyses.Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-015-0153-4) contains supplementary material, which is available to authorized users.
Highlights
Acute lymphoblastic leukemia (ALL) is not a single uniform disease
In GTGbanding cryptic balanced and unbalanced translocations, derivative chromosomes, isochromosomes, interstitial deletions, inverted duplications and/or numerical aberrations were identified in 34 % of the studied Copy number (CN)-ALL cases by means of molecular cytogenetics
It is well known that when using banding karyotyping cryptic chromosomal aberrations may be missed due to several reasons: (i) sensitivity of chromosomal banding techniques is limited, even in case of good chromosomal morphology, to aberrations being at least 10 Mb in size, (ii) aberrations may be cryptic or masked, i.e. they are not resolvable due to a similar or identical G-banding with trypsin-Giemsa (GTG)-banding pattern and/ or poor chromosome morphology, and (iii) metaphases may be difficult to obtain and to evaluated as chromosomes may not be well-spread, clumsy or appearing as fuzzy with indistinct margins; even numerical aberrations may be missed [6, 13, 17]
Summary
Acute lymphoblastic leukemia (ALL) is not a single uniform disease It consists of several subgroups with different cytogenetic and molecular genetic aberrations, clinical presentations and outcomes. Detectable structural or numerical chromosomal abnormalities are detected in ~50 % of ALL cases. Such aberrations have prognostic significance [1, 6]. Complex karyotypes, including three to five or more chromosomal abnormalities, are typically found in ~5 % of ALL cases and are associated with an adverse outcome [10]. Malignant bone marrow of T-ALL patients shows a normal karyotype more frequently than those of B-ALL patients In those cases cytogenetic markers cannot be determined and therapeutic decisions may be hampered
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