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

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

doi:10.3389/fcell.2021.764275

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

Front Cell Dev Biol. 2021 Nov 3:9:764275. doi: 10.3389/fcell.2021.764275. eCollection 2021.

Authors

Yuyang Feng^{1

2}, Surui Yao^{1

2}, Zhening Pu³, Han Cheng^{1

2}, Bojian Fei⁴, Jian Zou³, Zhaohui Huang^{1

2}

Affiliations

¹ Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, China.
² Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, China.
³ Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.
⁴ Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.

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.

Keywords: DNA repair; KIT; PDGFRA; gastrointestinal stromal tumors; metabolism; mutation; whole exome sequencing.