Diagnosis of intrachromosomal amplification of chromosome 21 (<scp>iAMP</scp>21) by molecular cytogenetics in pediatric acute lymphoblastic leukemia

Duployez, Nicolas; Boudry-Labis, Elise; Decool, Gauthier; Grzych, Guillaume; Grardel, Nathalie; Chahla, Wadih Abou; Preudhomme, Claude; Roche‐Lestienne, Catherine

doi:10.1002/ccr3.357

Cited by 6 publications

(2 citation statements)

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“…Reports on MLPA relevance in diagnostics are contradictory. A few publications considering application of MLPA in diagnostic setting of primary aberrations proved inferiority when compared with FISH assay that is undeniably standard method for detection of hyperdiploidy with chromosome 21 gain or ETV6-RUNX1 fusion, with just several methods, e.g., real-time PCR, karyotyping, and SNP array being appreciated aid (Sinclair et al 2011; Duployez et al 2015; Fuka et al 2015; Kim et al 2016; Luskin et al 2017). In contrary, different publications argue that MLPA match results with FISH, CISH array, and qPCR in cases with single-gene CNV detection (Benard-Slagter et al 2017).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, several downsides, e.g., semi quantitative results, requirement of high concentration of good quality DNA, cannot be overlooked. A few studies attempted to settle whether MLPA is reliable method in CNVs diagnostics and if it mirrors accurately results from FISH assay; however, conclusions were inconsistent (Garcia et al 2013; Duployez et al 2015; Fuka et al 2015; Ivanov Öfverholm et al 2016; Wang et al 2016; Benard-Slagter et al 2017; Ittel et al 2017; Yang et al 2017).…”

Section: Introductionmentioning

confidence: 99%

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MLPA as a complementary tool for diagnosis of chromosome 21 aberrations in childhood BCP-ALL

et al. 2019

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Chromosome 21 abnormalities are the most frequent genetic findings in childhood B cell precursor acute lymphoblastic leukemia (BCP-ALL) cases. Majority of patients are effectively diagnosed with fluorescence in situ hybridization (FISH) and karyotyping; however, some cases may require additional tools to be used. Bone marrow samples of 373 childhood BCP-ALL patients were tested for chromosome 21 copy number variations (CNVs) with Multiplex Ligation-dependent Probe Amplification (MLPA) P327 array. Results from MLPA and cytogenetics were compared between groups according to the type of abnormality found on chromosome 21. Out the group of 235 patients, chromosome 21 multiplication was found by FISH assay in 56 cases (23.81%), ETV6-RUNX1 fusion in 34 (14.47%) and iAMP21 in 3 (1.28%) children, remaining 142 (60.43%) patients had no known chromosome 21 aberration. Median peak ratios of all tested probes in MLPA in aforementioned groups were 1.47 (IQR 1.28–1.77) vs. 1.00 (IQR 1.00–1.09) vs. 2.79 (IQR 1.97–2.83) vs. 1.00 (1.00–1.11), respectively. Aforementioned peak ratio of ETV6-RUNX1 fusion group was similar with patients of no known chromosome 21 aberration (p = 0.71). Interestingly, both groups differed from patients with chromosome 21 multiplication (p < 10−5) and with iAMP21 (p < 10−5). All cases of iAMP21 were correctly recognized by MLPA. MLPA seems to be good additional tool in the diagnostic process of chromosome 21 CNVs, especially in cases with iAMP21.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MLPA as a complementary tool for diagnosis of chromosome 21 aberrations in childhood BCP-ALL

et al. 2019

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Prognostic Impact of Somatic Copy Number Alterations in Childhood B-Lineage Acute Lymphoblastic Leukemia

et al. 2020

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The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Gao

Ryan

Iacobucci

et al. 2023

Blood

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Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remain incompletely understood. Here, using integrated whole genome and transcriptome sequencing of 124 iAMP21-ALL patients, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL according to patterns of copy number alteration and structural variation. This large dataset enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which are differentially expressed compared to non-iAMP21-ALL cases, and including multiple genes implicated in the pathogenesis of acute leukemia: CHAF1B, DYRK1A, ERG, HMGN1 and RUNX1. Using multimodal single cell genomic profiling, including single cell whole genome sequencing of two cases, we documented clonal heterogeneity and genomic evolution, formally demonstrating that acquisition of the iAMP21-chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

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Diagnosis of intrachromosomal amplification of chromosome 21 (iAMP21) by molecular cytogenetics in pediatric acute lymphoblastic leukemia

Cited by 6 publications

References 6 publications

MLPA as a complementary tool for diagnosis of chromosome 21 aberrations in childhood BCP-ALL

MLPA as a complementary tool for diagnosis of chromosome 21 aberrations in childhood BCP-ALL

Prognostic Impact of Somatic Copy Number Alterations in Childhood B-Lineage Acute Lymphoblastic Leukemia

The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

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