Abstract
Aneuploidy occurs within a significant proportion of childhood B-cell acute lymphoblastic leukemia (B-ALL). Some copy number variations (CNV), associated with novel subtypes of childhood B-ALL, have prognostic significance. A total of 233 childhood B-ALL patients were enrolled into this study. Focal copy number alterations of ERG, IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A/2B, and the Xp22.33/Yp11.31 region were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA). The MLPA telomere kit was used to identify aneuploidy through detection of whole chromosome loss or gain. We carried out these procedures alongside measurement of DNA index in order to identify, aneuploidy status in our cohort. MLPA telomere data and DNA index correlated well with aneuploidy status at higher sensitivity than cytogenetic analysis. Three masked hypodiploid patients, undetected by cytogenetics, and their associated copy number neutral loss of heterozygosity (CN-LOH) were identified by STR and SNP arrays. Rearrangements of TCF3, located to 19p, were frequently associated with 19p deletions. Other genetic alterations including iAMP21, IKZF1 deletions, ERG deletions, PAX5AMP, which have clinical significance or are associated with novel subtypes of ALL, were identified. In conclusion, appropriate application of MLPA aids the identifications of CNV and aneuploidy in childhood B-ALL.
Highlights
Aneuploidy occurs within a significant proportion of childhood B-cell acute lymphoblastic leukemia (B-ALL)
We show that Multiplex Ligation-dependent Probe Amplification (MLPA) and DNA index (DI) are useful in its detection, as confirmed by single-nucleotide polymorphism (SNP) arrays and short tandem repeats (STR)
MLPA and DI are superior to traditional cytogenetics, due to the shorter turn-around time, irrespective of mitotic index and improved sensitivity
Summary
Aneuploidy occurs within a significant proportion of childhood B-cell acute lymphoblastic leukemia (B-ALL). Multiplex Ligation-dependent Probe Amplification (MLPA) is a sensitive method based upon the multiplex polymerase chain reaction and capillary electrophoresis that detects multiple copies of around 50 different genomic DNA targets. It has the advantage of lower price and quicker turn-around time than DNA arrays for identification of the important genetic alterations and is widely used for detection of the important copy number changes in A LL6,7. High hyperdiploidy with greater than 50 chromosomes comprises up to 30% of childhood B-ALL and most commonly involves gains of chromosomes X, 4, 10, 14, 17 and 2 18 It is associated with a good outcome, even in patients with induction failure[9]. Ph-like and iAMP21-ALL have been proposed as novel subtypes of B-ALL in the recent WHO classification of hematologic malignancies, due to their poor prognostic a ssociations[28]
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