RAS pathway mutations as a predictive biomarker for treatment adaptation in pediatric B-cell precursor acute...

Area of Science:

• Oncology
• Genetics
• Pediatric Hematology

Background:

• RAS pathway mutations are implicated in relapse and chemotherapy resistance in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
• Comprehensive data on subclonal mutations' frequency and prognostic impact in defined BCP-ALL subgroups are limited.

Purpose of the Study:

• To investigate the frequency, prognostic value, and therapeutic implications of RAS pathway mutations in pediatric BCP-ALL.
• To analyze clonal versus subclonal mutations and their association with treatment response and outcome.

Main Methods:

• Targeted deep sequencing of 13 RAS pathway genes in 461 pediatric BCP-ALL patients at diagnosis and 19 diagnosis-relapse pairs.
• Ex vivo drug sensitivity testing with prednisolone, vincristine, and trametinib.
• Correlation analysis of mutation status with clinical risk stratification and patient outcomes.

Main Results:

• RAS pathway mutations were found in 44.2% of patients, with 24.1% having clonal mutations.
• Mutation frequencies varied significantly across BCP-ALL subtypes, being highest in high hyperdiploid and BCR-ABL1-like cases.
• Clonal RAS mutations, but not subclonal ones, correlated with unfavorable outcomes and were more common at relapse.
• RAS-mutated cells showed ex vivo resistance to prednisolone and vincristine but sensitivity to the MEK inhibitor trametinib.

Conclusions:

• RAS pathway mutations are frequent in pediatric BCP-ALL, with clonal mutations serving as a marker for unfavorable prognosis.
• These findings highlight the potential of MEK inhibitors, like trametinib, for treating specific pediatric BCP-ALL patient groups.
• Targeted sequencing and analysis of RAS pathway mutations can inform risk stratification and personalized treatment strategies.