Copy Number Changes and Allele Distribution Patterns of Chromosome 21 in B Cell Precursor Acute Lymphoblastic Leukemia

Abstract

Chromosome 21 is the most affected chromosome in childhood acute lymphoblastic leukemia. Many of its numerical and structural abnormalities define diagnostically and clinically important subgroups. To obtain an overview about their types and their approximate genetic subgroup-specific incidence and distribution, we performed cytogenetic, FISH and array analyses in a total of 578 ALL patients (including 26 with a constitutional trisomy 21). The latter is the preferred method to assess genome-wide large and fine-scale copy number abnormalities (CNA) together with their corresponding allele distribution patterns. We identified a total of 258 cases (49%) with chromosome 21-associated CNA, a number that is perhaps lower-than-expected because ETV6-RUNX1-positive cases (11%) were significantly underrepresented in this array-analyzed cohort. Our most interesting observations relate to hyperdiploid leukemias with tetra- and pentasomies of chromosome 21 that develop in constitutionally trisomic patients. Utilizing comparative short tandem repeat analyses, we were able to prove that switches in the array-derived allele patterns are in fact meiotic recombination sites, which only become evident in patients with inborn trisomies that result from a meiosis 1 error. The detailed analysis of such cases may eventually provide important clues about the respective maldistribution mechanisms and the operative relevance of chromosome 21-specific regions in hyperdiploid leukemias.

Hyperdiploidy: the longest known, most prevalent, and most enigmatic form of acute lymphoblastic leukemia in children

“…Although constitutional trisomy 21 is by far the most common leukemia-predisposing factor, it is odd that classical HD forms are significantly underrepresented in this condition. To the best of our knowledge, none of the other aneuploid leukemia types have ever been reported in Down syndrome patients either [10,[26][27][28]]. Yet, once formed, the karyotype patterns of such classical HD cases resemble exactly the ones, which are seen in constitutionally normal patients.…”

“…In children, such "double hit" events comprise 2-3% of all HD cases, but they are 10-15 times more common in adults and therefore make up half of the total 13% of classical HD cases [31]. Although there are even a few mono-or bi-clonal nonclassical and/or hyperhaploid cases that concur with a t(9;22), we are not aware of any hypodiploid and/or near-triploid ones with such a constellation [28,32,33].…”

Optical Genome Mapping Identifies Novel Recurrent Structural Alterations in Childhood ETV6::RUNX1+ and High Hyperdiploid Acute Lymphoblastic Leukemia

“…To detect CN alterations and CN neutral loss of heterozygosity (CNN‐LOH), all 60 leukemia samples were analyzed using SNP‐arrays. For 18 leukemia cases, the CytoScan HD array (Thermo Fisher Scientific, Waltham, MA) was used as described 21 . The data were initially aligned to GRCh37 and a lift‐over to GRCh38 was performed for downstream analysis.…”

“…For 18 leukemia cases, the CytoScan HD array (Thermo Fisher Scientific, Waltham, MA) was used as described. 21 The data were initially aligned to GRCh37 and a lift-over to GRCh38 was performed for downstream analysis. The remaining 42 leukemia cases were analyzed using the Illumina CytoSNP-12 v2.1 array (Illumina, San Diego, CA) according to the manufacturer’s protocol.…”

Case Report: Refractory Cytopenia With a Switch From a Transient Monosomy 7 to a Disease-Ameliorating del(20q) in a NHEJ1-Deficient Long-term Survivor

“…This array comprises 2,670,000 markers, including 750,000 single nucleotide polymorphism probes (Applied Biosystems ™ , Thermo Fisher Scientific, Waltham, MA, USA). We obtained the data from a commercial service provider and analyzed them in-house with the Chromosome Analysis Suite (ChAS; Applied Biosystems ™ , ThermoFisher Scientific) software package version 4.1 as described previously in detail (22). Overall, six percent of the autosomal genome was homozygous, indicating consanguinity in the family.…”