Clinical and pathological features DNMT3A, FLT3, KIT, NPM1, NRAS, TP53 and wT1 genes mutations detection in acute myeloid leukemia patients aged 15-45 years old

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Abstract

The frequency of acute myeloid leukemia (AML) increases with age, respectively, the range of identified gene mutations and the pathways involved carcinogenesis can vary and affect the prognosis of treatment. The aim of the study was to estimate the frequency of mutations in DNMT3A, FLT3, KIT, NPM1, NRAS, TP53 and WT1 genes in acute myeloid leukemia (AML) patients (pts) aged 15-45 years old using direct automatic sequencing technique. Bone marrow and peripheral blood samples obtained from 36 AML pts aged 15 to 45. Distribution of the pts according to FAB-classification was as follows: AML M0 - 2, M1 - 1, M2 - 15, М3 - 2, M4 - 11, M4eo - 2, M5 - 2, blastic plasmacytoid dendritic cell neoplasm-1. Detection of mutations in ASXL1, DNMT3A, FLT3, KIT, NPM1, NRAS, TP53 and WT1 genes performed by automatic direct sequencing technique. The average frequency of functionally significant mutations in all investigated genes among the treated AML pts was 41,7 % (n=15), including 6 cases (40,0 %) with unfavorable cytogenetics, 6 cases (54,5 %) with normal karyotype, 3 cases (37,5 %) with favorable cytogenetics. These data correspond to the average frequency of point mutation in AML with normal and abnormal karyotype. Average frequency of mutations in FLT3 gene exons 12-15 and 19-21 - 21,9 %, NRAS gene exons 1-4 - 13,0 %, WT1 gene exons 6-9 - 11,1%, NPM1 gene exons 9-12 was 10,7 %, KIT gene exons 7-12 and 16-19 - 10,0 %, DNMT3A exons 18-26 - 7,1 %, TP53 gene exons 4-11 - 0,0 %. Multiple point mutations in investigated genes detected in 13.9 % AML specimens (usually KIT gene non-synonymous substitution c. 1621 А>С). Cryptic gene mutations detection using direct sequencing technique allowed to clarify the prognostic stratification of AML from groups of favorable and intermediate prognosis in 36,8 % (n=7). Thus, using of cytogenetic and additional molecular genetic research, a favorable prognosis of overall survival was established in 6 cases (16,7 %), intermediate - in 10 cases (27,8 %), adverse - in 18 cases (50,0 %), and unspecified - in 2 (5,6 %).

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About the authors

A. V Vinogradov

Ural State Medical University; Sverdlovsk Regional Clinical Hospital № 1

A. V Rezaykin

Ural State Medical University

S. V Sazonov

Ural State Medical University; Institute of Medical Cell Technologies

A. G Sergeev

Ural State Medical University

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