Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia

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 copynumber 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.copy number alterations ͉ single-nucleotide-polymorphism (SNP) ͉ microarray ͉ candidate gene resequencing ͉ loss-of-heterozygosity (LOH)

Gene expression profiling in MDS and AML: potential and future avenues

“…79 In contrast to ALL, the analysis of CNAs in AML has yielded only a small number of CNAs in most genomes of adult and pediatric AML patients, and the spectrum of AML-associated CNAs seems to be mainly non-recurrent. [80][81][82] These findings collectively illustrate the enormous genetic heterogeneity of AML and suggest that the potential of the extensive catalogs of CNAs might be better exploited by future integrative analyses.…”

IDH1 and IDH2 mutations are rare in pediatric myeloid malignancies

“…Furthermore, a previously reported genome-wide study of pediatric AML revealed that, in contrast to our AML patients with IDH2 mutation, pediatric de novo AML was characterized by a very low burden of genomic alterations. 7 These clinical and cytogenetic data suggest that pediatric AML with t(8;21) and IDH2 mutation might be a specific subtype of AML with complex chromosomal abnormalities and poor prognosis. Thus, our result has important clinical and pathological implications regarding the role of IDH2 mutations in the development of AML.…”

L’ETO se resserre sur les leucémies aiguës mégacaryoblastiques

“…Chez l'enfant, deux sous-groupes sont identifiés et représentent moins de 50 % des patients : (1) les LAM7 associées à la translocation t(1;22)(p13;q13) et à l'expression de la fusion OTT-MAL [3,4] décrite dans ces colonnes en 2009 [5] ; (2) celles qui se développent chez les patients porteurs d'une trisomie 21 constitutionnelle associée à des mutations du gène codant pour le facteur de transcription GATA-1 [6]. Les résul-tats d'une analyse génomique récente indiquent que les LAM7 pédiatriques présentent en moyenne 9,3 altérations structurelles par échantillon par comparaison avec 2,4 en moyenne pour les LAM en général et suggèrent l'existence d'autres anomalies chromosomiques [7]. Caractérisation génétique : le séquençage haut-débit du transcriptome permet l'identification de nouvelles anomalies chromosomiques (gauche : représentation en cercle des anomalies génomiques de structure) comme la fusion entre les gènes ETO2 et GLIS2 résultant d'une inversion du chromosome 16 (droite).…”