Differences in Cyto- and Molecular Genetic Abnormalities between Children

Abstract

Young children (defined as <2 years old) with acute myeloid leukemia (AML) do not differ in outcome when compared with older children with AML. Previously, distinct cytogenetic aberrations specific for AML in young children have been reported, such as t(7;12), and t(1;22), which is found exclusively in FAB M7. Moreover, young children with AML are characterized by a high frequency of 11q23-rearrangements. However, so far, no information is available on differences in the molecular genetic background of these two age groups. We therefore retrospectively investigated the distribution of different cytogenetic and molecular aberrations in a large cohort (n=435) of pediatric AML cases, of which 75 (17%) were young children. The predominant cytogenetic aberration in infant AML consisted of 11q23-rearrangements, which occurred in 44% of young children versus 17% in older children (p=<0.005), without differences in the distribution of 11q23-translocation partners. We also found significant differences in other cytogenetic subgroups of AML between young and older children, i.e. normal karyotype, 5% vs. 18%, respectively (p=0.008) and complex karyotype, 12% vs. 5% (p=0.03). t(7;12) (n=3) and t(8;16) (n=3) were only detected in young children, in contrast to t(15;17) (n=16) and t(8;21) (n=44), which were only seen in older children. Patients were also screened for molecular abnormalities, including the mutational hotspots of c-KIT (n=229), FLT3 (n=230), N-RAS (n=187), K-RAS (n=187), PTPN11 (n=216), MLL-partial tandem duplications (MLL-PTD) (n=240) and NPM1 (n=291). In the overall cohort, a significantly different age distribution was found for NPM1 mutations (0% young vs. 9% in older children; p=0.05) and FLT3-ITD (0% vs. 21%, respectively; p=0.005). Mutations in the other genes showed no clear correlation with age. Several non-random associations between molecular and cytogenetic abnormalities were detected. 89% of c-KIT mutations were associated with core-binding factor AML in children ≥2 years old. In young children, 2/4 c-KIT-mutated cases were associated with an MLL-rearrangement. NPM1 and FLT3-ITD mutations in older children were significantly correlated with normal karyotype AML (57% of NPM1 mutations, and 75% of FLT3/ITD; p=<0.005). In young children, 71% of RAS mutations were associated with an 11q23-rearrangement vs. 28% in older children (p=0.08). In older children however, 41% of the RAS mutations were associated with a normal karyotype. These data suggest that young children with AML are characterized by differences in the type and frequency of cytogenetic and molecular genetic abnormalities when compared with older children with AML, possibly reflecting differences in underlying biology between these age-groups. These differences may become clinically relevant in the era of molecularly targeted therapy.