ARTICLE ABSTRACT
Gastrointestinal stromal tumors (GISTs) with KIT exon 11 deletions involving in codons 557–558 (KIT Δ557–558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other KIT exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and global DNA hypomethylation only in high-risk malignant GISTs with KIT Δ557–558. Whole-genome sequencing revealed that the high-risk malignant GISTs with KIT Δ557–558 (12 cases) had more structural variations (SVs), single nucleotide variants, and insertions and deletions compared with the low-risk, less malignant GISTs with KIT Δ557–558 (6 cases) and the high- (6 cases) or low-risk (6 cases) GISTs with other KIT exon 11 mutations. The malignant GISTs with KIT Δ557–558 showed higher frequency and significance in copy number (CN) reduction on chromosome arms 9p and 22q, and 50% of them had loss of heterozygosity or CN-dependent expression reduction in CDKN2A. Additionally, SVs with driver potential were detected in 75% of them, in which AKT3 and MGMT were recurrently identified. Genome-wide DNA methylation and gene expression analyses showed global intergenic DNA hypomethylation, SNAI2 upregulation, and higher expression signatures, including p53 inactivation and chromosomal instability, as characteristics of malignant GISTs with KIT Δ557–558 that distinguished them from other GISTs. These genomic and epigenomic profiling results revealed that KIT Δ557–558 mutations are associated with increased genomic instability in malignant GISTs.
