J Gastric Cancer.  2020 Mar;20(1):29-40. 10.5230/jgc.2020.20.e2.

Genetic Characterization of Molecular Targets in Korean Patients with Gastrointestinal Stromal Tumors

• Park J
• Yoo HM
• Sul HJ
• Shin S
• Lee SW
• Kim JG

• KMID: 2471923
• DOI: http://doi.org/10.5230/jgc.2020.20.e2

Abstract

PURPOSE
Gastrointestinal stromal tumors (GISTs) frequently harbor activating gene mutations in either KIT or platelet-derived growth factor receptor A (PDGFRA) and are highly responsive to several selective tyrosine kinase inhibitors. In this study, a targeted next-generation sequencing (NGS) assay with an Oncomine Focus Assay (OFA) panel was used for the genetic characterization of molecular targets in 30 Korean patients with GIST.
MATERIALS AND METHODS
Using the OFA that enables rapid and simultaneous detection of hotspots, single nucleotide variants (SNVs), insertion and deletions (Indels), copy number variants (CNVs), and gene fusions across 52 genes relevant to solid tumors, targeted NGS was performed using genomic DNA extracted from formalin-fixed and paraffin-embedded samples of 30 GISTs.
RESULTS
Forty-three hotspot/other likely pathogenic variants (33 SNVs, 8 Indels, and 2 amplifications) in 16 genes were identified in 26 of the 30 GISTs. KIT variants were most frequent (44%, 19/43), followed by 6 variants in PIK3CA, 3 in PDGFRA, 2 each in JAK1 and EGFR, and 1 each in AKT1, ALK, CCND1, CTNNB1, FGFR3, FGFR4, GNA11, GNAQ, JAK3, MET, and SMO. Based on the mutation types, majority of the variants carried missense mutations (60%, 26/43), followed by 8 frameshifts, 6 nonsense, 1 stop-loss, and 2 amplifications.
CONCLUSIONS
Our study confirmed the advantage of using targeted NGS with a cancer gene panel to efficiently identify mutations associated with GISTs. These findings may provide a molecular genetic basis for developing new drugs targeting these gene mutations for GIST therapy.

Keyword

Ion torrent sequencing; KIT gene; Gastrointestinal stromal tumors; Next-generation sequencing; Mutation

MeSH Terms

DNA
Gastrointestinal Stromal Tumors*
Gene Fusion
Genes, Neoplasm
Humans
Molecular Biology
Mutation, Missense
Protein-Tyrosine Kinases
Receptors, Platelet-Derived Growth Factor
DNA
Protein-Tyrosine Kinases
Receptors, Platelet-Derived Growth Factor

Figure

• 

  Fig. 1 Frequencies of somatic mutation types detected in the various genes by the Oncomine Focus DNA Assay in 26 GISTs. Gene identities are depicted on the x-axis, and frequency of mutations on the y-axis.GIST = gastrointestinal stromal tumor.

• 

  Fig. 2 Distribution of somatic mutation types detected for each patient by Oncomine Focus DNA Assay in 26 GISTs. Individual patients are depicted on the x-axis, and identity of genes on the y-axis. Yellow box, amplification called; green box, frameshift mutation called; violet box, stop-loss mutation called; red box, nonsense mutation called; indigo box, missense mutation called; white box, no mutation called.GIST = gastrointestinal stromal tumor; PDGFRA = platelet-derived growth factor receptor A; NIH = National Institutes of Health.

• 

  Fig. 3 Distribution of mutations in KIT and PDGFRA functional domains. Somatic mutations in KIT and PDGFRA identified in our study are shown. Boxes represent functional domains: I–V, 5 immunoglobulin-like domain; TM, transmembrane domain; JM, juxtamembrane domain; TK1, tyrosine kinase domain 1; KI, kinase insert domain; TK2, tyrosine kinase domain 2. The type of mutation detected within the domains are indicated above.GIST = gastrointestinal stromal tumor; PDGFRA = platelet-derived growth factor receptor A.

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