Mutations ofNPM1gene inde novoacute myeloid leukaemia: determination of incidence, distribution pattern and identification of two novel mutations in Indian population

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Mutations in the nucleophosmin (NPM1) gene have been recently described to occur in about one-third of acute myeloid leukaemias (AMLs) and represent the most frequent genetic alteration currently known in this subset, specially in those with normal karyotype. This study explored the prevalence and clinical profile ofNPM1mutations in a cohort of 200 Indian adult and children with AML.NPM1mutations were observed in 19.5% of all population and 34.2% of those with normal karyotype. Adults had a significantly higher incidence ofNPM1mutations than children [38 of 161 (23.6%) vs. 1 of 39 (2.5%),p= 0.002].NPM1mutations were significantly associated with normal karyotype (p= 0.001), high WBC count (p= 0.034), AML-M4 subtype (p = 0.039) and a gradient increase of mutation rate with the increase in age groups. Sequence analysis of 39 mutated cases revealed typical mutations (types A, B, D, Nm and H*) as well as two novel variations (types F1 and F2). Majority of the patients had mutation type A (69.2%), followed by B (5.1%), D (15.3%), H* (2.5%) and Nm (2.5%) all involving COOH terminal of theNPM1protein. In conclusion, this study represents the first report of NPM1 mutation from Indian population and confirms that the incidence of NPM1 mutations varies considerably globally, with slightly lower incidence in Indian population compared to western countries. The current study also served to identify two novelNPM1mutants that add new insights into the heterogeneity of genomic insertions at exon 12. More ongoing larger studies are warranted to elucidate the molecular pathogenesis of AML that arises in this part of the world. Furthermore, we believe that in light of its high prevalence worldwide, inclusion ofNPM1mutation detection assay in diagnostic evaluations of AML may improve the efficacy of routine genetic characterization and allow assignment of patients to betterdefined risk categories.

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