Novel Genetic Variations in Acute Myeloid Leukemia in Pakistani Population.

Saba Shahid,Aiysha Abid,Misha Sohail,Saima Siddiqui,Shariq Ahmed,Ishtiaq Ahmad Khan,Muhammad Shakeel,Tahir Shamsi

doi:10.3389/fgene.2020.00560

Abstract

Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion of blast cells that exhibit great genetic heterogeneity. In this study, we describe the mutational landscape and its clinico-pathological significance in 26 myeloid neoplasm patients from a South Asian population (Pakistan) by using ultra-deep targeted next-generation DNA sequencing of 54 genes (∼5000×) and its subsequent bioinformatics analysis. The data analysis indicated novel non-silent somatic mutational events previously not reported in AML, including nine non-synonymous and one stop-gain mutations. Notably, two recurrent somatic non-synonymous mutations, i.e., STAG2 (causing p.L526F) and BCORL1 (p.A400V), were observed in three unrelated cases each. The BCOR was found to have three independent non-synonymous somatic mutations in three cases. Further, the SRSF2 with a protein truncating somatic mutation (p.Q88X) was observed for the first time in AML in this study. The prioritization of germline mutations with ClinVar, SIFT, Polyphen2, and Combined Annotation Dependent Depletion (CADD) highlighted 18 predicted deleterious/pathogenic mutations, including two recurrent deleterious mutations, i.e., a novel heterozygous non-synonymous SNV in GATA2 (p.T358P) and a frameshift insertion in NPM1 (p.L258fs), found in two unrelated cases each. The WT1 was observed with three independent potential detrimental germline mutations in three different cases. Collectively, non-silent somatic and/or germline mutations were observed in 23 (88.46%) of the cases (0.92 mutation per case). Furthermore, the pharmGKB database exploration showed a missense SNV rs1042522 in TP53, exhibiting decreased response to anti-cancer drugs, in 19 (73%) of the cases. This genomic profiling of AML provides deep insight into the disease pathophysiology. Identification of pharmacogenomics markers will help to adopt personalized approach for the management of AML patients in Pakistan.

Highlights

Acute myeloid leukemia (AML) is the most frequent form of acute leukemia in adults with a poor survival rate of about 5 years only (Horton and Huntly, 2012; Cancer Genome Atlas Research Network et al, 2013)
The deleterious impact of non-synonymous variants was assessed with SIFT, Polyphen2, and Combined Annotation Dependent Depletion (CADD), as described previously (Shakeel et al, 2018)
We appreciate the patients who participated in this study. This is the first report of a comprehensive analysis of somatic as well as germline mutations in AML from Pakistan using next-generation DNA sequencing technology

Summary

Introduction

Acute myeloid leukemia (AML) is the most frequent form of acute leukemia in adults with a poor survival rate of about 5 years only (Horton and Huntly, 2012; Cancer Genome Atlas Research Network et al, 2013) It is caused by pathogenic variations in normal progenitor myeloid hematopoietic cells, leading to altered differentiation, proliferation, and self-renewal capability of the cells (Papaemmanuil et al, 2016). The improved AML prognosis associated with mutated NPM1 and biallelic mutations in the CEBPA have resulted in a change in the disease definition (May Green et al, 2010; Hollink et al, 2011) These recent advances have changed the classification and introduced molecular subtypes of the AML with gene mutations (NPM1 and CEPBA) by the recommendation of WHO classification of hematopoietic tumors in 2008 (Campo et al, 2008). Further studies on genetic landscape of AML have expanded the mutational spectrum where TET2, DNMT3A, NPM1, SRSF2, and ASXL1 genes are mutated frequently in elderly people (Prassek et al, 2018)

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