Molecular Evaluation of DNMT3A and IDH1/2 Gene Mutation:Frequency, Distribution Pattern and Associations with Additional Molecular Markers in Normal Karyotype Indian Acute Myeloid Leukemia Patients

Mutations in the DNMT3A and IDH genes represent the most common genetic alteration after FLT3/NPM1in acute myeloid leukemia (AML). We here analyzed the frequency and distribution pattern of DNMT3A andIDH mutations and their associations with other molecular markers in normal karyotype AML patients. Fortyfivepatients were screened for mutations in DNMT3A (R882), IDH1 (R132) and IDH2 (R140 and R172) genesby direct sequencing. Of the 45 patients screened, DNMT3A and IDH mutations were observed in 6 (13.3%)and 7 (15.4%), respectively. Patients with isolated DNMT3A mutations were seen in 4 cases (9%), isolatedIDH mutations in 5 (11.1%), while interestingly, two cases showed both DNMT3A and IDH mutations (4.3%).Nucleotide sequencing of DNMT3A revealed missense mutations (R882H and R882C), while that of IDH revealedR172K, R140Q, R132H and R132S. Both DNMT3A and IDH mutations were observed only in adults, with ahigher frequency in males. DNMT3A and IDH mutations were significantly associated with NPM1, while trendstowards higher coexistence with FLT3 mutations were observed. This is the first study to evaluate DNMT3A/IDH mutations in Indian patients. Significant associations among the various molecular markers was observed,that highlights cooperation between them and possible roles in improved risk stratification.