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Genomic Characterization of RTK-RAS Pathway Alterations in Juvenile Myelomonocytic Leukemia Through Whole-Exome
Harsh Goel1, Ravi Kumar Majhi2, Jagdish Prasad Meena2
1Laboratory Oncology Unit, Dr. B.R.A. Institute of Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India.
Background/Objectives:
Juvenile 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.
Methods:
We 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.
Results:
Alteration of the RTK-RAS pathway was found in 77.1% of patients. PTPN11 (23%), NRAS (20%), and KRAS (14%) were the most frequently altered genes, followed by PTEN (11%) and FLT3, ROS1, FGFR4, ERBB2, and EGFR (9% each). Domain mapping of protein sequences identified the grouping of mutations within the conserved functional domains of the proteins. The alterations in receptor tyrosine kinase genes demonstrated a significant degree of co-occurrence, while the alterations in canonical JMML genes showed mutual exclusivity. PTPN11, NRAS, ROS1, and FGFR4 were top driver genes based on driver gene analysis. Functional enrichment analysis revealed significant enrichment of receptor tyrosine kinase signaling, Ras/MAPK and PI3K-AKT pathways. The mutational signatures were mostly SBS5-like, with enrichment of C>T transitions, indicative of endogenous mutational processes. Drug-gene interaction analysis identified EGFR, ALK, ROS1, ERBB2, FLT3, FGFR4, and PDGFRA as highly interconnected and potentially actionable therapeutic targets.
Conclusions:
These 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.
