Molecular Aberrations in 107 Children with Myelodysplastic Syndrome (MDS).

The integrative non-random collaboration of type II and type I mutations which induce maturation arrest and hyperproliferation respectively, has been extensively studied in myeloid malignancies. So far, information on the involvement of these aberrations in pediatric MDS is lacking.

We studied the occurrence of genetic aberrations in an international cohort of pediatric MDS patients (n=44 primary de novo MDS, n=63 secondary MDS. Karyotypes were studied and the hotspot regions of the NPM1, CEPBA, FLT3, N-RAS, K-RAS, BRAF, PTPN11, c-KIT, RUNX1, P53, ASXL1, NUP98, IDH1 and 2, DNMT3A and TET2 genes were screened for mutations.

Type I aberrations were found in 8/107 (7.5%) patients (4/44 primary MDS, 4/63 secondary MDS): mutations in FLT3–ITD (n=3), N-RAS (n=2), K-RAS (n=2) and PTPN11 (n=1). No mutations were found in the FLT3-TKD, c-KIT, P53 and BRAF gene. Type II aberrations were identified in 17/107 (16%) (4/44 primary MDS, 13/63 secondary MDS): MLL-rearrangements (n=2), RUNX1-rearrangement (n=1), RUNX1 mutations (n=7), duplications in the CEBPα gene (n=5), NPM1 gene mutation (n=1) and NUP98 translocation (n=1). We identified ASXL1 mutations (n=2) and DNMT3A mutations (n=1), but no TET2, IDH1 and IDH2 mutations were found in any of the pediatric MDS cases. Only two secondary MDS patients carried both a type I and a type II mutation (NRAS + RUNX1 mutation and ASXL1 + RUNX1 mutation).

In 9% of de novo MDS a type I aberration was found and in 9% a type II aberration, all being mutually exclusive. In secondary MDS type I aberrations occurred in 6% and type II aberrations in 24% of the cases (including the mutations in genes regulating the histone function and DNA methylation). In only 2% of all cases (secondary MDS only) a collaborative type I and II mutation was found.

This study indicates that in childhood MDS, in contrast to adult MDS, the currently known molecular, especially the histone modificating and DNA methylating influencing, aberrations are of minor importance in the pathogenesis of childhood MDS.

No relevant conflicts of interest to declare.