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Objectives:  The study aims to investigate genetic characterization of molecular targets and clinicopathological features with gastrointestinal stromal tumors based on targeted next-generation sequencing.   Materials and Methods:  We selected 106 patients with GISTs from Sir Run Run Shaw Hospital between July 2019 and March 2021. FFPE samples and paired blood samples were obtained from these patients who underwent excision of the tumor. A customized targeted-NGS panel of nine GIST-associated genes was designed to detect variants in the coding regions and the splicing sites of these genes.   Results:  In total, 106 patients with a GIST were included in the study which presented with various molecular driver alterations in this study.  KIT  mutations occurred most often in GISTs (94/106, 95.92%), followed by point mutations in  PDGFRA .  KIT  or  PDGFRA  mutations were detected to be mutually exclusive in the GIST. A total of eight patients with wide-type  KIT/PDGFRA  were characterized as WT-GISTs, according to clinical diagnosis which included six quadruple-WT GISTs, 1  BRAF -mutant, and 1  NF1 -mutant GIST. In  KIT  exon 11, the most common mutation type was the codon Mutation (in-frame deletion or indels), whereas the missense mutation was the dominant type in  KIT  exon 13 and  KIT  exon 17. All variations in  KIT  exon 11 observed in this study were concentrated at a certain position of codon 550 to codon 576. Mutation in  KIT  exon 9 was mostly located at codon 502–503. Two germline pathogenic mutations were detected: NF1-R681* and KRAS-T58I. NF1-L591P was a germline mutation to be identified for the first time and is not recorded in the database. The frequency of driving mutations differed between the primary anatomical site in the GIST ( p  = 0.0206).  KIT  exon 11 mutants had a lower proliferation index of Ki67 (68.66%,≤5%), while 50.00% of  KIT  exon 9 mutants had the Ki67 status greater than 10%.   Conclusion:  The occurrence and development of a GIST is driven by different molecular variations. Resistance to TKIs arises mainly with resistance mutations in  KIT  or  PDGFRA  when they are the primary drivers. Targeted NGS can simultaneously and efficiently detect nine GIST-related gene mutations and provide reference for clinicians’ individualized diagnosis and treatment. Our results have important implications for clinical management.

frontiers in genetics

Molecular Portrait of GISTs Associated With Clinicopathological Features: A Retrospective Study With Molecular Analysis by a Custom 9-Gene Targeted Next-Generation Sequencing Panel