Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia

Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2009; 106(31):12944-9. DOI: 10.1073/pnas.0903142106
Source: PubMed


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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    • "Paired datasets, GSE14471 and GSE15714, containing gene expression and SNP genotyping data, respectively, from 111 pediatric acute myeloid leukemia samples (of which 109 were typed successfully), were analyzed for an association between CT gene expression and MTHFR 677 genotype distribution [16]. A principal component analysis using 44 probesets corresponding to 9 CT gene families was performed for the expression dataset. "
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    • "), indicate that AML contains fewer genetic alterations than do other malignancies. Paediatric AML in particular contains few genomic alterations, with only 2Á4 somatic copy-number alterations per leukaemia and no copy-number alterations in about one-third of cases, suggesting that the development of AML may require fewer genetic alterations than other malignancies (Radtke et al, 2009). Nevertheless, novel lesions have been identified, such as mutations in the IDH1 and DNMT3A genes (Mardis et al, 2009; Ley et al, 2010; Andersson et al, 2011). "
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