Genomic Characterization of RTK-RAS Pathway Alterations in Juvenile Myelomonocytic Leukemia Through Whole-Exome Sequencing.

BACKGROUND/

objectivesJuvenile myelomonocytic leukemia (JMML) is a rare and very aggressive pediatric myelodysplastic/myeloproliferative neoplasm with molecular heterogeneity and constitutive activation of the RAS signaling pathway. The aim of this study was to identify the mutational landscape, driver genes, mutational signatures, functional pathways, and therapeutic targets of mutations that affect receptor tyrosine kinases (RTKs) and RAS pathways in JMML.

methodsWe collected tumor and matched buccal swab samples from 35 patients with JMML and performed whole-exome sequencing. Variants were called using GATK-Mutect2 and annotated with ANNOVAR. Mutational profiling, co-occurrence analysis, protein domain mapping, and driver gene identification were performed using maftools and OncodriveCLUST. DGIdb was used to explore drug-gene interactions, MutationalPatterns was used for the characterization of mutational signatures, and the clusterProfiler package was used for the functional enrichment analyses.

resultsAlteration of the RTK-RAS pathway was found in 77.1% of patients.

conclusionsThese findings expand the molecular landscape of JMML and underscore the importance of aberrant RTK-RAS signaling in disease pathogenesis. The identification of recurrent and potentially druggable RTK alterations provides a rationale for future precision medicine approaches in JMML.