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.

Fig. 1.

Chromosome gains detected by SNP array analysis in 74 cases of high hyperdiploid childhood ALL. Xf denotes gain of the X chromosome in females; Xm in males. “Trisomy” and “Tetrasomy” of Xm and Y correspond to one and two extra copies of these chromosomes, respectively. Chromosomes X, 4, 6, 10, 14, 17, 18, and 21 were all gained in more than 70% of the cases; chromosome 21 was gained in 100% of the cases. Extra copies of chromosomes 8 and 5 were present in 36% and 26% of the cases, respectively, whereas all other chromosomes were gained in <20% of the 74 cases. Tetrasomies were seen for chromosomes 4, 8, 10, 14, 18, 21, and X, and pentasomy was seen for chromosome 21 only.

Fig. 2.

Overview of acquired genetic imbalances and UPIDs detected by SNP array analysis in 74 cases of high hyperdiploid childhood ALL. Each line corresponds to an aberration in the chromosome on the left. Thin lines correspond to aberrations detected in one case; thicker lines indicate aberrations detected in eight cases. Blue lines denote gains, red lines denote losses, and green lines denote UPIDs. This figure was made using the Genome-Wide Viewer software, freely available at http://www.well.ox.ac.uk/~jcazier/GWA_View.html.

Fig. 3.

Examples of SNP array data from case 56. Top panels show log2 ratios along the chromosomes. Each dot represents the log2 ratio of one marker. A log2 ratio of zero corresponds to a normal, diploid copy number. Increased and decreased log2 ratios correspond to gained and deleted regions, respectively. Lower panels show B allele frequencies (BAF), which are calculated as (signal intensity for allele B)/(signal intensities for allele A + allele B). Homozygous SNPs have a value of 0 or 1, and heterozygous SNPs a value of 0.5 in a diploid chromosome segment. (A) Chromosome 17. Trisomy for this chromosome is apparent as an increased average log2 ratio and BAF values of 0, ~0.33, ~0.67, and 1.0, where the middle values correspond to the heterozygous SNPs. (B) Chromosome 12. Disomy for this chromosome is apparent as an average log2 ratio of ~0 and BAF values of 0, ~0.5, and 1.0. A hemizygous deletion is seen in 12p12.3–13.3 including ETV6, visible as a log2 ratio of less than −0.5 and complete loss of heterozygosity (i.e., BAF values of 0 and 1.0 only). The panels were extracted from the BeadStudio 3.1.2.0 software with Illumina Genome Viewer 3.2.9.