Mutational and genomic landscape of acute myeloid leukemia: Insights from a South Asian targeted next-generation sequencing cohort

Objectives: Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy, yet comprehensive genomic data from South Asian populations remain limited. Population-specific mutation profiling is critical for accurate risk stratification and optimal use of targeted therapies. This study characterizes the genomic landscape of AML in a South Asian cohort using next-generation sequencing (NGS). Material and Methods: We analyzed 167 AML patients with pathogenic variants using the Myeloid HAEM DNA-RNA NGS panel (Oncomine Myeloid Research Assay) (Thermo Fisher Scientific, Waltham, Massachusetts), covering 40 DNA-based genes and 29 fusion transcripts. Variants were interpreted according to American Society of Hematology (ASH)/Association for Molecular Pathology/European Hematology Association (EHA) recommendations and classified using the OncoKB Tier system, which stratifies alterations based on their therapeutic, diagnostic, and prognostic relevance into Tier I (strong clinical significance), Tier II (potential clinical significance), and Tier III (unknown clinical significance). Mutation frequencies, co-mutation patterns, and age distributions of genetic aberrations were also analyzed. Results: Tier I alterations constituted 31.35% of pathogenic findings and were enriched for established driver mutations, including FLT3, NPM1, IDH1, IDH2, and recurrent fusion genes such as PML-RARA and RUNX1-RUNX1T1, reflecting their direct therapeutic and prognostic relevance. Tier II variants accounted for 67.33% of cases and involved genes with emerging or context-dependent clinical significance, including ASXL1, BCOR, BRAF, CEBPA, DNMT3A, EZH2, KRAS, NRAS, and RUNX1, frequently observed in co-mutation patterns. Tier III variants, such as STAG2 and RB1, represented 1.32% of pathogenic findings for which definite clinical relevance remains uncertain. Conclusion: This study delineates a distinct genomic landscape of South Asian AML, characterized by a high burden of Tier I driver mutations, and a substantial proportion of Food and Drug Administration-approved actionable alterations of 23.4% was noted. The unique co-mutational patterns highlighted the complexity and heterogeneity of the mutational spectrum in leukemia. The findings highlight the clinical utility of comprehensive NGS-based profiling combined with Tier-based variant stratification to enhance risk assessment, refine prognostication, and enable precision-guided therapeutic decision-making in underrepresented populations.