Mutational landscape of gastrointestinal stromal tumors using next-generation sequencing of a 73-gene panel

Mutational analysis guides therapeutic decision-making for patients with advanced-stage gastrointestinal stromal tumors (GISTs).

A total of 491 patients with GISTs were retrospectively included, and their genomic profiles were determined by targeted NGS of 73 or 1,021 gene panels.

KIT mutations were identified in 84.7% (416/491) of patients with GISTs, and PDGFRA mutations were identified in 4.5% (22/491) of patients. Among the patients with KIT mutant-GISTs, most had KIT mutations in exon 11 (81.3%, 338/416). PDGFRA mutations were located mainly in exon 18 (77.3%, 17/22). In the remaining 11% of patients with GISTs without KIT or PDGFRA mutations (wild-type GISTs), BRAF and NF1 were the most commonly mutated genes. Compared with KIT/PDGFRA-mutant GISTs, wild-type GISTs were associated with younger age, a greater proportion of female patients, and lower levels of copy number variations. Notably, the concomitant alterations of KIT/PDGFRA-mutant or wild-type GISTs were similar when sequencing data from a 73-gene panel and a 1,021-gene panel were analyzed. The genetic landscape of patients with treatment-naïve GISTs at different locations was described by using a 73-gene panel, and compared with patients with gastric GISTs, patients with nongastric GISTs had higher levels of copy number variations but a lower proportion of PDGFRA mutations. Analysis of the genomic profiles before and after imatinib treatment revealed KIT T670I mutation, as well as ATM and JAK2 mutations, as potential underlying mechanisms of resistance.

Using a 73-gene panel, we characterized the molecular characteristics of GISTs and revealed a correlation with their clinical features. Moreover, KIT/PDGFRA-dependent and KIT/PDGFRA-independent mechanisms underlying resistance to imatinib were explored. Overall, our 73-gene panel is sufficient for clinical application in cases of GISTs.