Unmasking Additional Mutations: A Single Institution Study in Myeloproliferative Neoplasms.
Key claim: Comprehensive 75-gene NGS at initial MPN evaluation reveals additional pathogenic mutations in roughly one-fifth of patients—including high-molecular-risk co-mutations in driver-positive cases and clonal or alternative-myeloid findings in driver-negative cases—improving disease classification and risk stratification.
Abstract
BACKGROUND/OBJECTIVES: Myeloproliferative neoplasms (MPNs) are chronic myeloid malignancies characterized by substantial genetic heterogeneity. Although routine molecular evaluation focuses on canonical driver alterations (, and), additional somatic mutations have important diagnostic and prognostic implications. METHODS: We retrospectively analyzed 1209 consecutive patients who underwent peripheral blood next-generation sequencing (NGS) for suspected or established MPNs using a comprehensive 75-gene DNA/RNA panel. RESULTS: Canonical driver alterations were identified in 141 patients, while 1068 were driver-negative. Retrospective analysis demonstrated that 251 patients (21%) harbored at least one additional pathogenic or likely pathogenic mutation that was not routinely reported. Among driver-positive patients, 57 of 141 (40%) carried clinically relevant co-mutations, including high-molecular-risk genes such as, and. Furthermore, 194 of 1068 (18%) driver-negative patients harbored additional pathogenic mutations, several of which supported clonal hematopoiesis or alternative myeloid neoplasms. Peripheral blood and bone marrow molecular findings demonstrated high concordance (R= 0.87). CONCLUSIONS: These findings indicate that comprehensive NGS performed at the time of initial evaluation provides clinically relevant genomic information beyond canonical driver mutations, improves disease classification and risk stratification, and may facilitate earlier diagnosis and personalized management of patients with suspected MPNs.
Why this matters
Across MPN subtypes, prognosis and transformation risk are increasingly defined by non-driver co-mutations (ASXL1, EZH2, SRSF2, IDH1/2) rather than JAK2/CALR/MPL alone, yet many centers still test only driver genes at diagnosis. This study quantifies the yield of comprehensive up-front NGS — roughly one in five patients gains actionable classification or risk-stratification information — reinforcing that broad panel testing should be part of baseline MPN workup regardless of subtype. It also addresses the underrecognized driver-negative population, where NGS may reveal alternative myeloid diagnoses that reshape natural-history expectations.