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

Yuyang Feng,Han Cheng,Jian Zou,Bojian Fei,Zhening Pu,Zhaohui Huang,Surui Yao

doi:10.3389/fcell.2021.764275

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.

Highlights

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive tract, and are mainly driven by activating mutations in KIT or plateletderived growth factor A (PDGFRA), accounting for 0.1–3% of all gastrointestinal tumors
As the main drivers of GIST, gain-of-function mutations in KIT or PDGFRA have been identified in 85–95% of GIST tumors
High drug resistance and relapse ratios were observed in GIST patients, especially those with risk factors, suggesting that additional genes and pathways may be related to the development, progression and chemoresistance of GIST

Summary

Introduction

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive tract, and are mainly driven by activating mutations in KIT ( known as CD117) or plateletderived growth factor A (PDGFRA), accounting for 0.1–3% of all gastrointestinal tumors. The status of KIT or PDGFRA is closely associated with GIST development, progression and therapeutic response. GISTs harboring the same KIT/PDGFRA mutations often display different malignant features and response to therapy, suggesting that there are other potential GIST-related genes that influence the biological phenotypes or prognosis of GIST patients (Li and Raut, 2019); little is known about the mutation profiles at the genome level in GIST. Screening Novel Mutations in GIST case No Gender Age Tumor site S01 M S02 S04 S05 S07

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