The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia

Kajsa Paulsson and colleagues performed whole-genome and/or whole-exome sequencing of 51 cases of high hyperdiploid pediatric acute lymphoblastic leukemia, which is characterized by a massive nonrandom gain of chromosomes. They found that high hyperdiploidy arose early during leukemogenesis and was the main leukemogenic event. High hyperdiploid (51–67 chromosomes) acute lymphoblastic leukemia (ALL) is one of the most common childhood malignancies, comprising 30% of all pediatric B cell–precursor ALL. Its characteristic genetic feature is the nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21, with individual trisomies or tetrasomies being seen in over 75% of cases, but the pathogenesis remains poorly understood. We performed whole-genome sequencing (WGS) ( n = 16) and/or whole-exome sequencing (WES) ( n = 39) of diagnostic and remission samples from 51 cases of high hyperdiploid ALL to further define the genomic landscape of this malignancy. The majority of cases showed involvement of the RTK-RAS pathway and of histone modifiers. No recurrent fusion gene–forming rearrangement was found, and an analysis of mutations on trisomic chromosomes indicated that the chromosomal gains were early events, strengthening the notion that the high hyperdiploid pattern is the main driver event in this common pediatric malignancy.