FLT3 mutation incidence and timing of origin in a population case series of pediatric leukemia

We screened and sequenced FLT3 mutations (point mutations and internal tandem duplications, ITDs) among 517 childhood leukemia patients, and assessed whether these mutations occurred before or after birth using sensitive "backtracking" methods.We determined a mutation prevalence of 9 of 73 acute myeloid leukemias (AMLs, 12%) and 9 of 441 acute lymphocytic leukemias (ALLs, 2%). Among AMLs, FLT3 mutations were more common in older patients, and among ALLs, FLT3 mutations were more common in patients with high hyperdiploidy (3.7%) than those without this cytogenetic feature (1.4%). Five FLT3 ITDs, one deletion mutation, and 3 point mutations were assessed for their presence in neonatal Guthrie spots using sensitive real-time PCR techniques, and no patients were found to harbor FLT3 mutations at birth.FLT3 mutations were not common in our population-based patient series in California, and patients who harbor FLT3 mutations most likely acquire them after they are born.Certain, but not all, chromosome translocations in childhood leukemia are known to be present at birth. This phenomenon of prenatal origin was initially presumed from twin studies where it was observed that mono-amniotic twins always harbored the same translocations (reviewed in [1]). In addition, several studies have shown that specific mutations found at diagnosis in children with leukemia were present at birth, that is, "backtracked" to neonatal Guthrie Cards (blood spots used for newborn screens) (reviewed in [2]). The MLL rearrangement in infant ALL "backtracks" in nearly all cases and TEL-AML1 is found on 75% of Guthrie cards matched to leukemia cases with the translocation [3-5]. The E2A-PBX1 fusion generated by the t(1;19) translocation is a likely exception, with a postnatal origin [6], along with possibly others. These results collectively support a "two hit" model of leukemia, with one hit early in life or in utero, and another at a later date in temporal proximity to leukemia diagnosis.The FLT3