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

Abstract

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.

Development and validation of a prognostic model to predict the prognosis of patients with colorectal gastrointestinal stromal tumor: A large international population-based cohort study

“…First, it is a retrospective analysis using a public database and, in this case, the avoidance of selection bias is difficult. Second, our nomogram provided individual predictions of OS for patients with five clinicopathological factors and CSS for patients with seven clinicopathological factors, lacking other additional variables which was reported to be significantly prognostic factor for the prognosis of patients with GISTs, such as mitotic rate, tumor rupture, Ki67 index (52)(53)(54). However, the SEER database does not contain these variables and future studies will need to incorporate them further into the analysis.…”

Exploring Perforated Jejunal GIST: A Rare Case Report and Review of Molecular and Clinical Literature

“…The implementation of next-generation sequencing (NGS) has significantly enhanced our understanding of GISTs [26]. Historically, 85-90% of GISTs were identified with activating mutations in the KIT or PDGFRA genes.…”

Mutation and Expression Analysis of Gastrointestinal Stromal Tumor Associated Genes Spectrum in a Pakistani Male through Comprehensive Next-generation Sequencing

“…These genes in uence cell division, cell death, survival, and differentiation by controlling the RAS and PI3K signaling pathways. These are the disease's primary pathogens and the therapeutic basis for the effectiveness of Tyrosine Kinase inhibitors currently in use (Brčić et al, 2021;Qian et al, 2022). Deletions, insertions, and missense mutations arise in these genes.…”

“…Manzur et al forged this term to relate an anatomically extensive continuum of tumors of the gut (Mavroeidis et al, 2018). They are considered rare tumors of the gastrointestinal tract and account for 0.1-3% of digestive tract malignancies (Al-Share et al, 2021; Qian et al, 2022). The pacemaker cells of the viscera, the interstitial cells of Cajal (ICC), involved in gastrointestinal tract vermiculation, are believed to be the cells of origin for these tumors.…”

“…There's no sex speci cation. As per the topographical disparities and due to lack of proper diagnosis, the factual incidence rate of GIST varies from as low as 4.3-6.8 cases per million to as high as 19-22 cases per million, with almost 5000 new cases being diagnosed each year in the USA (Mei et al, 2018). The incidence of familial autosomal dominant GIST is only about 5%, while most of the cases are sporadic (Al-Share et al, 2021; Wu et al, 2019).…”