1. Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies
- Author
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Maria Dobre, Cristina Enache, Mihaela Gaman, Silvana Angelescu, Oana Stanca, Aurora Arghir, Horia Bumbea, Sorina Mihaela Papuc, Nicoleta Berbec, Ana-Maria Vladareanu, Diana Cisleanu, E Andrus, Alina Erbescu, Andrei Colita, Viola Maria Popov, Ion Dumitru, and Diana Ozunu
- Subjects
Neuroblastoma RAS viral oncogene homolog ,medicine.medical_specialty ,NPM1 ,DNA Copy Number Variations ,Computational biology ,QH426-470 ,Biology ,Article ,DNA Methyltransferase 3A ,GTP Phosphohydrolases ,Molecular cytogenetics ,03 medical and health sciences ,0302 clinical medicine ,Mutation Rate ,Genetics ,medicine ,Humans ,Genetic Testing ,Copy-number variation ,Genetics (clinical) ,detection yield ,mutational screening ,Cytogenetics ,High-Throughput Nucleotide Sequencing ,Membrane Proteins ,Myeloid leukemia ,Histone-Lysine N-Methyltransferase ,Leukemia, Myeloid, Acute ,chromosomal abnormalities ,KMT2A ,fms-Like Tyrosine Kinase 3 ,030220 oncology & carcinogenesis ,biology.protein ,somatic mutations ,Nucleophosmin ,Myeloid-Lymphoid Leukemia Protein ,copy number variants ,030215 immunology ,Comparative genomic hybridization - Abstract
Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients, in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the NPM1 gene, followed by DNMT3A, FLT3 and NRAS. An unexpected co-occurrence of KMT2A translocation and DNMT3A-R882 was identified, alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.
- Published
- 2021