Comprehensive High-Sensitivity Mutation Profiling in MPNs: Diagnostic and Prognostic Implications

Abstract

Simple Summary This study evaluated ultra-deep error-corrected next-generation sequencing (NGS) in 134 patients with myeloproliferative neoplasms (MPNs) to determine its diagnostic and prognostic value. Ultra-deep sequencing detected many low-variant-allele-frequency (VAF < 5%) mutations that conventional methods could miss, including 25% of CALR, 43% of MPL, and 82% of TP53 mutations. In contrast, most JAK2 mutations had higher VAFs and were reliably detected by standard testing. During leukemic transformation, all TP53 mutations showed VAFs > 5%, suggesting clonal expansion during disease progression. Lower JAK2 p.V617F VAFs were associated with patients who remained untreated, indicating potential clinical relevance for treatment decisions. Additional mutations such as ASXL1 and SRSF2 were observed in patients with disease progression. Overall, the findings suggest that panel-based ultra-deep NGS improves mutation detection, enhances diagnostic sensitivity, and may provide valuable prognostic information for MPN management, although larger prospective studies are needed to confirm these results.