Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia

Abstract

High hyperdiploid acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. It is characterized by gain of chromosomes, typically +X, +4, +6, +10, +14, +17, +18, and +21, +21; little is known about additional genetic aberrations. Approximately 20% of the patients relapse; therefore it is clinically important to identify risk-stratifying markers. We used SNP array analysis to investigate a consecutive series of 74 cases of high hyperdiploid ALL. We show that the characteristic chromosomal gains are even more frequent than previously believed, indicating that karyotyping mistakes are common, and that almost 80% of the cases display additional abnormalities detectable by SNP array analysis. Subclonality analysis strongly implied that the numerical aberrations were primary and arose before structural events, suggesting that step-wise evolution of the leukemic clone is common. An association between duplication of 1q and +5 was seen (P = 0.003). Other frequent abnormalities included whole-chromosome uniparental isodisomies (wUPIDs) 9 and 11, gain of 17q not associated with isochromosome formation, extra gain of part of 21q, deletions of ETS variant 6 (ETV6), cyclin-dependent kinase inhibitor 2A (CKDN2A) and paired box 5 (PAX5), and PAN3 poly(A) specific ribonuclease subunit homolog (PAN3) microdeletions. Comparison of whole-chromosome and partial UPID9 suggested different pathogenetic outcomes, with the former not involving CDKN2A. Finally, two cases had partial deletions of AT rich interactive domain 5B (ARID5B), indicating that acquired as well as constitutional variants in this locus may be associated with pediatric ALL. Here we provide a comprehensive characterization of the genetic landscape of high hyperdiploid childhood ALL, including the heterogeneous pattern of secondary genetic events.

Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011

“…36 Both ADD3 and PAN3 have been reported to play a role in ALL -ADD3 is a NUP98 partner in T-ALL 37 and significantly associated with a gene expression cluster group with poor outcome in high risk BCP ALL 38 and PAN3 is recurrently deleted in high hyperdiploidy ALL. 39 Prior to this report, deletions of ATP10A have not been clearly associated with ALL. However, when reviewing supplementary data published by Mullighan et al 4 , we identified two high risk ALL cases with deletion of this gene.…”

“…4 This agrees well with previous 14 immunogenotypic, FISH, and cytogenetic studies of ALL. [7][8][9][10][11][12] However, in contrast to prior SNP array-based analyses, 4,13,14 we identified fewer clones arising from ancestral clones and more identical clones at the time of the event. This may partly be due to the fact that we also analyzed IF samples, of which 3 of 4 showed identical clones, indicating that the time to this event is too short for evolution to occur.…”

“…,-2,-3,-4,-5,+6,+10,-12,-13,-14,-15,-16,-18,-19,-20 # The original karytypes of these cases have previously been reported. [1][2][3][4][5][6][7][8][9][10][11] Supplementary rs10251980 50366637 rs7785321 50418242 rs6964823 50460096 rs11980379 50469981 14Dx 12 1+0sc rs12313493 9175109 rs1012588 9270835 rs4575342 38663831 rs12308157 39421767 14Dx 18 1+0 rs7230788 22927757 rs10163652 22942497 rs5003540 23111439 rs8090239 23124693 14Dx 20 1+0sc rs6088244 32110204 rs3746460 32248163 qtel 14IF 7 1+0 rs10251980 50366637 rs7785321 50418242 rs6964823 50460096 rs11980379 50469981 14IF 12 1+0 rs12313493 9175109 rs1012588 9270835 rs4575342 38663831 rs12308157 39421767 14IF 18 1+0 rs7230788 22927757 rs10163652 22942497 rs5003540 23111439 rs8090239 23124693 14IF 20 1+0 rs6088244 32110204 rs3746460 32248163 The panels were extracted from the genome studio v2011.1 software (Illumina). Below the panels are the chromosomes involved.…”

“…A number of studies aiming at elucidating the underlying mechanisms for relapse has compared genetic features in paired diagnostic and relapse samples using conventional cytogenetic, 7,8 clone-specific polymerase chain reaction (PCR), 9,10 fluorescence in situ hybridization (FISH), 11,12 and single nucleotide polymorphism (SNP) array analyses, 4,[13][14][15][16][17] revealing that the relapsed clones can be identical to the ones seen at diagnosis, display additional changes (clonal evolution), or harbor both additional, identical as well as fewer changes (evolution from a preleukemic/ancestral clone). The two latter evolution patterns indicate outgrowth of therapy-resistant minor subclones.…”

“…The two latter evolution patterns indicate outgrowth of therapy-resistant minor subclones. 4,[9][10][11][12]16,17 In addition, high-resolution genomic profiling has identified genes, for example CDKN2A, ETV6, IKZF1, and EBF1, that are more frequently deleted in samples from patients who subsequently relapse than in samples from those remaining in fist complete remission (CR1). 4,13,14,18 However, whether these deletions serve as independent prognostic markers is still unclear.…”