Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs).

Abstract

Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in <i>KIT</i> and <i>PDGFRA</i> genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis. Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed. Both patients harbouring low-risk GISTs with different mutations (<i>PDGFRA</i> and <i>KIT</i>) shared homozygous germline pathogenic deletions in both <i>CFHR1</i> and <i>CFHR3</i> genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as <i>SLC25A24</i>. No particular pathogenic SNV shared by both patients was detected. Our study provides new insights into germline variants that can be associated with the development of GISTs, namely, <i>CFHR1</i> and <i>CFHR3</i> deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.