Identification of New Tumor-Related Gene Mutations in Chinese Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. As the main GIST drivers, gain-of-function mutations in KIT or PDGFRA are closely associated with not only tumor development and progression but also therapeutic response. In addition to the status of KIT and PDGFRA, little is known about other potential GIST-related genes. In this study, we identified the mutation profiles in 49 KIT-mutated GIST tumors using the whole exome sequencing (WES) method. Furthermore, some representative mutations were further validated in an independent GIST cohort using the SNaPshot SNP assay. We identified extensive and diverse mutations of KIT in GIST, including many undescribed variants. In addition, we revealed some new tumor-related gene mutations with unknown pathogenicity. By enrichment analyses of gene function and protein-protein interaction network construction, we showed that these genes were enriched in several important cancer- or metabolism-related signaling pathways, including PI3K-AKT,RTK-RAS, Notch, Wnt, Hippo, mTOR, AMPK, and insulin signaling. In particular, DNA repair-related genes, including MLH1, MSH6, BRCA1, BRCA2, and POLE, are frequently mutated in GISTs, suggesting that immune checkpoint blockade may have promising clinical applications for these GIST subpopulations. In conclusion, in addition to extensive and diverse mutations of KIT, some genes related to DNA-repair and cell metabolism may play important roles in the development, progression and therapeutic response of GIST.

Characterization of Aberrations in DNA Damage Repair Pathways in Gastrointestinal Stromal Tumors: The Clinicopathologic Relevance of γH2AX and 53BP1 in Correlation with Heterozygous Deletions of CHEK2, BRCA2, and RB1

“…However, RB1 (25%), as well as genes involved in the HRR (e.g., RAD51 in 18.8%) and Fanconi anemia (e.g., BRCA2 in 12.5%) pathways, were also recurrently hit by HetDels. These findings are largely in keeping with a recent whole-exome sequencing study on GISTs, which demonstrated a potential relationship between CNVs and DDR [ 34 ]. Therefore, the CNV-driven deregulation of DDR gene expression has been proposed as a mechanism of defective DNA repair, while sporadic pathogenic missense mutations of DDR genes, e.g., BRCA1, BRCA2, and POLE, were also identified in that study.…”

Correlation of treatment outcome in sanger/RT‑qPCR KIT/PDGFRA wild‑type metastatic gastrointestinal stromal tumors with next‑generation sequencing results: A single‑center report

“…The calculated TMB was low in all patients (less than 10 mutations/MB). These results are in accordance with the previous study by Chalmers et al (48) but differ from the results by Feng et al (49). High TMB correlates with the response to immune checkpoint inhibitors in solid tumors and pembrolizumab was approved for adults and children with TMB-high solid tumors (50).…”

hOGG1 rs1052133 Polymorphism and Prostate Cancer Risk: A Chinese Case-Control Study and Meta-Analysis

“…The site sequence of the hOGG1 rs1052133 polymorphism was obtained from the NCBI db SNP database. For each DNA sample, the hOGG1 rs1052133 polymorphism was detected by using the SNaPshot SNP assay by Shanghai Tianhao company (Shanghai Tianhao Industrial Co., Ltd., Shanghai, China) [ 25 , 26 ]. We used the Multiplex SNaPshot technology (Applied Biosystems, Foster City, CA, USA) to determine the genotype of hOGG1 gene.…”