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

UNLABELLED

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.

SIGNIFICANCE

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.