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. 2009 Aug 4;106(31):12944-9.
doi: 10.1073/pnas.0903142106. Epub 2009 Jul 27.

Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia

Ina Radtke  1 , Charles G Mullighan, Masami Ishii, Xiaoping Su, Jinjun Cheng, Jing Ma, Ramapriya Ganti, Zhongling Cai, Salil Goorha, Stanley B Pounds, Xueyuan Cao, Caroline Obert, Jianling Armstrong, Jinghui Zhang, Guangchun Song, Raul C Ribeiro, Jeffrey E Rubnitz, Susana C Raimondi, Sheila A Shurtleff, James R Downing
Affiliations

Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia

Ina Radtke et al. Proc Natl Acad Sci U S A. .

Abstract

Pediatric de novo acute myeloid leukemia (AML) is an aggressive malignancy with current therapy resulting in cure rates of only 60%. To better understand the cause of the marked heterogeneity in therapeutic response and to identify new prognostic markers and therapeutic targets a comprehensive list of the genetic mutations that underlie the pathogenesis of AML is needed. To approach this goal, we examined diagnostic leukemic samples from a cohort of 111 children with de novo AML using single-nucleotide-polymorphism microarrays and candidate gene resequencing. Our data demonstrate that, in contrast to pediatric acute lymphoblastic leukemia (ALL), de novo AML is characterized by a very low burden of genomic alterations, with a mean of only 2.38 somatic copy-number alterations per leukemia, and less than 1 nonsynonymous point mutation per leukemia in the 25 genes analyzed. Even more surprising was the observation that 34% of the leukemias lacked any identifiable copy-number alterations, and 28% of the leukemias with recurrent translocations lacked any identifiable sequence or numerical abnormalities. The only exception to the presence of few mutations was acute megakaryocytic leukemias, with the majority of these leukemias being characterized by a high number of copy-number alterations but rare point mutations. Despite the low overall number of lesions across the patient cohort, novel recurring regions of genetic alteration were identified that harbor known, and potential new cancer genes. These data reflect a remarkably low burden of genomic alterations within pediatric de novo AML, which is in stark contrast to most other human malignancies.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
DNA copy-number abnormalities in pediatric de novo AML. (A) Summary of CNA (log2 ratio) from a combined 100K and 500K Affymetrix SNP array analysis of diagnostic leukemia cells from 111 pediatric de novo AML patients. Each column represents a case and the 615K SNPs are arranged in rows according to chromosomal location. Cases are arranged by subgroup. Diploid regions are white. Blue represents deletion, red amplification (see color scale). Gross changes can be observed for example in chromosome 8 (10 cases with trisomy 8). (B) GISTIC (18) analysis of copy-number gains. (C) GISTIC analysis of copy-number losses. False discovery rate q values are plotted along the x axis with chromosomal position along the y axis. Altered regions with significance levels exceeding 0.25 (marked by vertical green line) are deemed significant. Five significant regions of amplification and 13 significant regions of deletion were identified. Chromosomal position and relevant genes are shown for each significant region on the right side of the plots. Genes indicated in blue are associated with known translocations, genes marked with * are cancer census genes (19).
Fig. 2.
Fig. 2.
Amplification of CCDC26 in pediatric AML. The genomic organization of CCDC26 is illustrated relative to the telomere (tel) and centromere (cent) of chromosome 8, with exons labeled by lowercase e, and an alternative transcript initiating from exon e1a. The vertical blue lines show the location of the SNPs on combined 100K and 500K Affymetrix arrays. The putative ORF encoded by exons e3 and e4 is shown by a dotted line with the arrowhead illustrating the direction for transcription. The vertical red arrow marks the integration site found in a retroviral integration screen of retinoic acid resistant myeloid cell lines (20). The green box represents the 10-kb lincRNA, identified in ref. . The extent of amplification across this genomic locus for each case is illustrated by a horizontal red line with the case ID number next to the line or the number of cases that contained large amplifications that included the entire locus. Two AML cell lines, HL-60 and NB-4, were also found to have focal amplification of this locus.
Fig. 3.
Fig. 3.
Integrated analysis of copy-number alterations, CN-LOH, and point mutations. Each column illustrates the results of the integrated mutational analysis for a single patient, with the patients grouped into the 7 genetic AML subtypes, which are color coded as illustrated. The rows depict the presence of mutations from sequence analysis (Top 13 rows) or copy-number alterations (Bottom 2 rows). The presence of a mutation in a gene is shown as a box, with the type of mutation indicated by the color of the box as shown. The presence of copy-number alterations is shown in the Bottom 2 rows with amplifications in red, and deletions in green, and the intensity of the color corresponding to the number of copy-number alterations according to the scale shown at bottom right.
Fig. 4.
Fig. 4.
Spectrum of number of lesions per case in pediatric AML and ALL. Percentage of cases containing zero (normal), 1, 2, 3, 4, 5, or >5 alterations based on cytogenetics, cytogenetics plus CNAs using 615K SNP arrays, or cytogenetics, 615K SNP arrays, and targeted gene resequencing of 25 candidate genes in A AML (n = 111 cases) and B ALL (n = 212, cases from refs. 4, 5).
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