Multi-Omic Landscape of Gastrointestinal Stromal Tumors in a Real-World Patient Cohort of 1,427 Cases.

Abstract

Gastrointestinal stromal tumor (GIST) is a genomically-driven neoplasm with a genetic profile that determines the clinical course of the disease. However, currently available molecular data is limited due to the rarity of the disease and does not fully capture GIST clinical and biological heterogeneity. To gain deeper insight into the molecular landscape of GIST, we performed a comprehensive multi-omic analysis (targeted panel, whole exome sequencing, whole transcriptomics) in a large real-world, multicenter cohort including 1,427 cases. Pathological review was undertaken in KIT/PDGFRA-wild type cases. Molecular findings were correlated with clinical data and insurance claims outcomes. There is a complex spectrum of multi-layered genetic events that converge in three GIST molecular subgroups: KIT-mutant, PDGFRA-mutant, and KIT/PDGFRA-wild-type. These alterations can only be captured using next-generation sequencing technologies, and are associated with clinical features, biological aggressiveness, and patient outcomes. Mutations in alternative genes, whether actionable or not, are seldom present and unlikely to contribute to tumor progression. By contrast, the cooperative effect of novel somatic copy number alterations may be required for GIST evolution and progression, in addition to the core set of events involved in the current cytogenetic model of tumorigenesis. This molecular landscape provides a broader molecular understanding of GIST and supports a widespread use of genetic profiling for patients' clinical management.