Abstract
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.
Highlights
Succinate dehydrogenase deficient (SDH-deficient) gastrointestinal stromal tumors (GISTs), as defined by the expression loss of the subunit B of the succinate dehydrogenase complex, account for approximately 20% to 40% of all KIT/PDGFRA wild-type (WT) GISTs and 5% of all GISTs [1]
The 3D projections in both principal component analysis (PCA) analyses showed that SDH-deficient GISTs distinctly separate from KIT-mutant GISTs, providing proof of an expression profile typical of this molecular subgroup and profoundly different from KIT-mutant GISTs, supporting the hypothesis that the two GIST molecular groups may derive from two distinct cell types or oncogenic programs (Figure 1A,B)
The analysis of differential expression (DE) was performed for both sample series to discover the set of genes that are significantly overexpressed or down-regulated in SDH-deficient GISTs
Summary
Succinate dehydrogenase deficient (SDH-deficient) gastrointestinal stromal tumors (GISTs), as defined by the expression loss of the subunit B of the succinate dehydrogenase complex, account for approximately 20% to 40% of all KIT/PDGFRA wild-type (WT) GISTs and 5% of all GISTs [1]. The SDH deficiency is mainly due to mutations in one of the four SDH mitochondrial complex subunits, SDHA, SDHB, SDHC, and SDHD [1,2,3]. 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. 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. 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
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