Spectrum of gene mutations identified by targeted next‐generation sequencing in Chinese leukemia patients

Abstract

Background Despite targeted sequencing have identified several mutations for leukemia, there is still a limit of mutation screening for Chinese leukemia. Here, we used targeted next‐generation sequencing for testing the mutation patterns of Chinese leukemia patients. Methods We performed targeted sequencing of 504 tumor‐related genes in 109 leukemia samples to identify single‐nucleotide variants (SNVs) and insertions and deletions (INDELs). Pathogenic variants were assessed based on the American College of Medical Genetics and Genomics (ACMG) guidelines. The functional impact of pathogenic genes was explored through gene ontology (GO), pathway analysis, and protein–protein interaction network in silico. Results We identified a total of 4,655 SNVs and 614 INDELs in 419 genes, in which PDE4DIP, NOTCH2, FANCA, BCR, and ROS1 emerged as the highly mutated genes. Of note, we were the first to demonstrate an association of PDE4DIP mutation and leukemia. Based on ACMG guidelines, 39 pathogenic and likely pathogenic mutations in 27 genes were found. GO annotation showed that the biological process including gland development, leukocyte differentiation, respiratory system development, myeloid leukocyte differentiation, mesenchymal to epithelial transition, and so on were involved. Conclusion Our study provided a map of gene mutations in Chinese patients with leukemia and gave insights into the molecular pathogenesis of leukemia.

Transcriptome analysis of primary adult B‐cell lineage acute lymphoblastic leukemia identifies pathogenic variants and gene fusions, and predicts subtypes for in depth molecular diagnosis

“…The SNV analysis also uncovered other SNVs, including multiple in the PDE4DIP gene in the one Ph + and the four KMT2Ar patient samples, with two or three different PDE4DIP SNVs detected in each sample (Figures 1D and Figure S2D). The biological significance of these is not known, but recurrent mutations in the PDE4DIP gene have been reported in different cancers, including leukemia 34 . As SNV analysis of RNA‐seq data can lead to false positive SNVs, clinically relevant SNVs should be validated on a case‐by‐case basis by targeted resequencing of genomic DNA from leukemic cells 35,36 .…”

“…The biological significance of these is not known, but recurrent mutations in the PDE4DIP gene have been reported in different cancers, including leukemia. 34 As SNV analysis of RNA-seq data can lead to false positive SNVs, clinically relevant SNVs should be validated on a case-by-case basis by targeted resequencing of genomic DNA from leukemic cells. 35,36 As a proof-of-principle, we performed next-generation sequencing (NGS) of PCR-amplified genomic DNA from the Rh007 PB sample as a representative leukemia sample (Figure S2B).…”

cAMP Signaling in Cancer: A PKA-CREB and EPAC-Centric Approach

“…Mutations in the phosphodiesterase 4Dinteracting protein (PDE4DIP) gene have also been found in NSCLC with leptomeningeal metastases [201]. Germline indels and single nucleotide variations in the PDE4DIP gene have been found in leukemia patients [202]. This PDE4DIP function is necessary for cell stability at the leading edge of migrating cells, and its influence on tumor cell motility and proliferation is vital in tumor development [203].…”

Exploration of Novel Genetic Evidence and Clinical Significance Into Hemifacial Microsomia Pathogenesis

“…Some evidence supportive of a possible underlying relation between these 3 genes and HFM pathogenesis can be sought in past studies. PDE4DIP was validated to be downregulated in acute myeloid leukemia patients32 and interact with Fyn phosphorylation-activated PKA kinase in glioblastoma cells 33…”

“…31 Some evidence supportive of a possible underlying relation between these 3 genes and HFM pathogenesis can be sought in past studies. PDE4DIP was validated to be downregulated in acute myeloid leukemia patients 32 and interact with Fyn phosphorylation-activated PKA kinase in glioblastoma cells. 33 ITGβ4 protein, coded by ITGB4 interacts with ITGβ4-binding protein intracellularly, inhibits TGF-β/Smad signaling, as well as reduces β-catenin expression and thus inhibits Wnt/β-catenin pathway 34 that modulates organogenesis, cell proliferation, differentiation, migration, bone formation, and maintenance.…”