Molecular evaluation of gene mutation profiles and copy number variations in pediatric acute myeloid leukemia

The objectives of this study were to investigate the mutation profiles of targeted genes and copy number variations (CNVs) in normal cytogenetics (CN) pediatric acute myeloid leukemia (AML).

This prospective study was conducted from October 2018 to December 2020. The next-generation sequencing (NGS) and chromosomal microarray analyses (CMA) were performed in pediatric CN-AML patients.

Out of 94 children (aged ≤18 years), 70 patients with AML (24 excluded) underwent conventional karyotyping/cytogenetic analyses. Forty-five (64.3%) of patients had abnormal/ recurrent cytogenetic abnormalities and 25 (35.7%) had normal cytogenetics. Twenty-three out of 25 CN-AML were further processed for gene mutation profile and CNVs using NGS and CMA, respectively. Twenty-two out of 23 (95.7%) patients were detected to have mutations in various genes. The common mutations were: NRAS, NPM1, CEBPA, KRAS, KIT, RUNX1, NOTCH1, WT1, GATA1, GATA2, FLT3, KMT2D, FLT3-TKD, and PHF6. Copy number variations (CNVs) were detected in nine patients (39%), and eight (34.8%) had a long contiguous stretch of homozygosity (LCSH) /loss of heterozygosity (LOH). An LCSH was detected on chromosomes 5, 7, 11, and 19. The gains were more common than losses (8 vs 2). The gains were observed on chromosomes 8, 9, 14, 19, 21, and 22, and the losses were detected on chromosomes 7 and 10. Monosomy was observed in three patients. Three patients (monosomy7, n = 2, and FLT-ITD, n = 1) were reclassified into the high-risk category. Post-induction, complete remission was achieved in all evaluable patients.

CN-AML patients have genetic abnormalities that can be detected by more advanced techniques like NGS and CMA. These genetic abnormalities play a role in risk stratification that may remain hidden in otherwise CN-AML.