Novel Genetic Variations in Acute Myeloid Leukemia in a South Asian Population

Introduction: Acute Myeloid Leukemia (AML) is a heterogeneous hematologic malignancy characterized by clonal expansion of blast cells. The prognosis, diagnosis, and treatment of AML have been transformed from histological findings to cytogenetic and genomic testing. We assessed the frequency and clinicopathologic significance of 54 genes in myeloid neoplasm patients by using targeted next-generation sequencing. Methods: Blood samples of 26 patients were collected from OPD at National Institute of Blood Diseases (NIBD). The myeloid sequencing panel of 54 genes (complete coding exons of 15 genes and exonic hotspots of 39 genes) was sequenced. The panel total coverage was 141 kb in genomic sequence. TruSight myeloid sequencing (Illumina, CA) libraries were prepared and runs were performed on a MiSeq (Illumina) genome sequencer. The generated data were analyzed by on-instrument software or TruSeq Amplicon® and BaseSpace Apps®. Results: The analysis with ANNOVAR showed total 295 variants comprises of 71 nonsynonymous SNVs (including 12 novels), three stop-gained SNVs (including two novel), two novel splice-site SNVs, and eleven frame-shift Indels (including seven novels) in at least one of the patients. Among 71 nonsynonymous, three driver non-synonymous mutations (rs121913535, rs121913529 in KRAS, rs121913250 in NRAS), and a driver non-frame shift insertion in EZH2 were found using the ParsSNP tool. In addition, three high frequency novel variants were also found including a heterozygous indels in FBXW7 in 92% of the cases, a heterozygous SNV in FBXW7 in 54% cases, and a heterozygous SNV in GATA2 in 42% cases. Conclusion: Genomic profiling of AML will provide novel insight in the diseases pathogenesis. Our findings demonstrate great heterogeneity of pathogenic/deleterious genetic variation in AML patients of this study. The deleterious alterations vary in different patients of AML. This highlights the usefulness of panel sequencing in cases where prognosis becomes challenging. In our study, the genes EZH2, BCOR, WT1, KRAS, KIT, DNMT3A, and CSF3R were found most frequently mutating. In addition, other genes having single mutation also conferred pathogenicity. These findings will provide a framework for assessing genetic predisposition of AML patients of South Asian region. No relevant conflicts of interest to declare.