title: 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.
abstract: Mutations in the DNMT3A and IDH genes represent the most common genetic alteration after FLT3/NPM1 in acute myeloid leukemia (AML). We here analyzed the frequency and distribution pattern of DNMT3A and IDH mutations and their associations with other molecular markers in normal karyotype AML patients. Forty- five patients were screened for mutations in DNMT3A (R882), IDH1 (R132) and IDH2 (R140 and R172) genes by 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%), isolated IDH 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 revealed R172K, R140Q, R132H and R132S. Both DNMT3A and IDH mutations were observed only in adults, with a higher frequency in males. DNMT3A and IDH mutations were significantly associated with NPM1, while trends towards 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.
authors.affiliation: Research and Development, SRL Ltd, Mumbai, India E-mail : brdas@srl.in.
authors.forename: Firoz
authors.initials: F
authors.lastname: Ahmad
authors.forename: Rupali
authors.initials: R
authors.lastname: Mohota
authors.forename: Savita
authors.initials: S
authors.lastname: Sanap
authors.forename: Swarna
authors.initials: S
authors.lastname: Mandava
authors.forename: Bibhu Ranjan
authors.initials: BR
authors.lastname: Das
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005260:Female; D006801:Humans; D007194:India; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D017422:Sequence Analysis, DNA; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3