Clinical Impact of Next-Generation Sequencing-Detected Mutations on Thrombotic Events in Myeloproliferative Neoplasms.
Key claim: In a cohort of 91 MPN patients profiled by a 78-gene NGS panel, JAK2/TET2 co-mutation was the strongest independent predictor of VTE, while ASXL1 and splicing factor mutations were associated with arterial events, bone marrow fibrosis, and inferior overall survival.
Abstract
INTRODUCTION: Myeloproliferative neoplasms (MPNs), encompassing polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are hematologic malignancies characterized by recurrent somatic mutations. Despite advances in next-generation sequencing (NGS), the genetic basis of thrombotic risk and bone marrow (BM) fibrosis in MPNs remains unclear. METHODS: Patients diagnosed with classical MPN at Trakya University Faculty of Medicine were retrospectively analyzed (2018-2025). Mutation profiling was conducted on BM aspirates using a 78-gene panel on the Illumina NextSeq platform, with clinically relevant variants (VAF ≥ 2%) interpreted via Qiagen Clinical Insight. RESULTS: Among 91 patients with MPN, the most frequent mutations were JAK2 (71.4%), TET2 (23.1%), DNMT3A (15.4%), ASXL1 (11%), and splicing factor mutations (SFMs; 12%). Arterial events occurred in 45.1% of patients and were associated with age (p < 0.001), higher Charlson Comorbidity Index (CCI; p < 0.001), ASXL1 (p:0.019), and SFMs (p:0.009). VTE occurred in 38.5% and was associated with JAK2 status and allele burden (p:0.004 and p:0.012 respectively), TET2 (p < 0.001), and SFMs (p:0.002); the JAK2/TET2 co-mutant subgroup had the highest risk of VTE risk in multivariable analysis (OR: 2.9, 95% CI: 1.4-5.7; p:0.002). Advanced BM fibrosis was associated with SFMs (p:0.018). Increased mutational burden correlated with both venous and arterial thrombosis (p:0.021 and p:0.044, respectively). In survival analyses, SFMs (HR: 5.2; p:0.008), ASXL1 (HR: 3.8; p:0.030), and PMF diagnosis (HR: 3.8; p:0.045) were associated with inferior overall survival (OS). CONCLUSION: Molecular profiling may provide clinically relevant thrombotic risk stratification in classical MPNs. JAK2/TET2 co-mutation was linked to VTE, while ASXL1 and SFMs were associated with adverse phenotypes including vascular events, BM fibrosis, and inferior OS.
Why this matters
This finding refines the mutation-to-phenotype map in MPN by showing that specific co-mutation patterns—not just driver status—stratify thrombotic risk by vascular bed (JAK2/TET2 → venous; ASXL1/splicing factors → arterial) and link the same high-risk lesions to fibrotic progression and reduced survival. It bridges previously siloed mechanism pages (TET2, ASXL1, thrombosis, fibrosis) and motivates NGS-informed thrombosis risk stratification beyond JAK2 allele burden alone.