NGS - A Tool to Identification Variants in Acute Myeloid Leukemia Patients

Acute Myeloid Leukemia (AML) is a cancer of the myeloid line of blood cells that is chemo-sensitive with the potential to be cured but exhibits high relapse rates, which reduces cure rates.

To identified somatic coding and noncoding variants that may contribute to leukemogenesis, researchers from the Kangwon National University tried to found some genetic changes relevance between the primary and relapse samples of a single patient or between the primary and relapse tumor samples from different patients by Using a whole genome sequencing (WGS) approach. 11 Korean AML patient samples sequencing results produce two different datasets: (1) the "SNU-p11" dataset, comprising only the 11 primary AML samples, and (2) the "SNU-pr5" dataset, containing five paired primary and relapse samples obtained from each of five individuals. Analysis databases including TWG30, TES193, Lawrence 134, and COSMIC census genes. A total of 187 genes with nonsynonymous SNVs were detected in the SNU-p11, 17 SNVs were detected in at least two other datasets, indicating that mutations in these genes might play critical roles in AML pathogenesis. A total of 41 mutated genes with nonsynonymous SNVs were detected in the SNU-pr5, 17 genes had previously been identified as AML-associated genes in other studies.

Fig. 1. Comparison of common variants between the SNU-p11 and TWG30 datasets.(Mol. Cells 2018; 41(5): 465-475)

Fig. 2. Profiles of commonly detected coding mutations between primary and relapse samples. (Mol. Cells 2018; 41(5): 465-475)

Four genes, SIN3A, C10orf53, PTPRR, and RERGL, were chosen form above-mentioned mutation based on: (1) commonly mutated genes, (2) genes carrying nonsynonymous substitutions with high variant allele frequencies (VAFs), (3) genes carrying novel SNVs, and (4) genes carrying highly conserved SNVs with a PhyloP score > 1.0, and their variants were validated via Sanger sequencing. Besides, a newly designed analysis method, "hot-zone" analysis—is very effective for detecting putative functional noncoding variants.

Fig. 3. Profiles of somatic nonsynonymous variants detected in both the paired primary and relapse samples. (Mol. Cells 2018; 41(5): 465-475)

Fig. 4. Survival differentiated by the expression levels of the four mutated genes. (Mol. Cells 2018; 41(5): 465-475)

Finally, SIN3A, a novel mutation which expression shows prognostic value in AML, was identified.

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