Gene Expression Landscape of SDH-Deficient Gastrointestinal Stromal Tumors

Background: About 20-40% of gastrointestinal stromal tumors (GISTs) lacking KIT/PDGFRA mutations show defects in succinate dehydrogenase (SDH) complex. This study uncovers the gene expression profile (GEP) of SDH-deficient GIST in order to identify new signaling pathways or molecular events actionable for a tailored therapy. Methods: We analyzed 36 GIST tumor samples, either from formalin-fixed, paraffin-embedded by microarray or from fresh frozen tissue by RNA-seq, retrospectively collected among KIT-mutant and SDH-deficient GISTs. Pathway analysis was performed to highlight enriched and depleted transcriptional signatures. Tumor microenvironment and immune profile were also evaluated. Results: SDH-deficient GISTs showed a distinct GEP with respect to KIT-mutant GISTs. In particular, SDH-deficient GISTs were characterized by an increased expression of neural markers and by the activation of fibroblast growth factor receptor signaling and several biological pathways related to invasion and tumor progression. Among them, hypoxia and epithelial-to-mesenchymal transition emerged as features shared with SDH-deficient pheochromocytoma/paraganglioma. In addition, the study of immune landscape revealed the depletion of tumor microenvironment and inflammation gene signatures. Conclusions: This study provides an update of GEP in SDH-deficient GISTs, highlighting differences and similarities compared to KIT-mutant GISTs and to other neoplasm carrying the SDH loss of function. Our findings add a piece of knowledge in SDH-deficient GISTs, shedding light on their putative histology and on the dysregulated biological processes as targets of new therapeutic strategies.

Automated summary

This study uncovered the gene expression profile of SDH-deficient GIST and identified characteristics such as increased expression of neural markers and activation of fibroblast growth factor receptor signaling. The study also revealed shared features with SDH-deficient pheochromocytoma/paraganglioma and depletion of tumor microenvironment and inflammation gene signatures. The findings provide new insights into the histology and dysregulated biological processes in SDH-deficient GISTs.