Mutational architecture defines disease behaviour in an Indian cohort of Myeloproliferative Neoplasms: Foundations...

Data on BCR::ABL1-negative MPN genomics in India are limited. We aimed to define mutational architecture and evaluate co-mutation burden for risk stratification.

We analysed 179 patients (median age 57 years; 36.3% ≤50 years). Targeted NGS covering relevant myeloid genes was performed in 104 patients (58%). Prognostic factors and latent molecular subgroups were evaluated using Cox proportional hazards and DBSCAN clustering.

Single-hit genotypes predominated (65.9%), but MF/pre-PMF showed ≥ 2 mutations in 42% and ≥ 3 in 18%. Double-hit status (≥1 driver + ≥1 DTA/MDS-HR) occurred in 26% and conferred a 4.87-fold mortality risk (p = 0.0132). TET2 independently predicted inferior OS (HR 11.83; p < 0.005). DBSCAN identified a poor risk JAK2 +CoMut subgroup (n = 29; 18.3% of NGS cohort) enriched for TET2/ASXL1 with median OS 3.3 years versus NR for the remaining cohort. Pre-PMF and MF cases had higher mutation burden and co-mutations (≥1 DTA/MDS-HR: 62% vs 15% in PV/ET). Survival differences were independent of WHO diagnostic labels, with molecular architecture alone consistently predicting outcomes across all clusters CONCLUSIONS: In this Indian MPN cohort, molecular architecture, not WHO label, dictated prognosis. The reproducible impact of high-risk co-mutations demonstrates both the feasibility and need for a genomics-first, tiered classification to guide risk stratification and therapy.