Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557-558 Deletion Mutations

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