Valentina Indio1, Angela Schipani2, Margherita Nannini3, Milena Urbini4, Alessandro Rizzo2, Antonio De Leo5, Annalisa Altimari6, Valerio Di Scioscio7, Daria Messelodi8, Giuseppe Tarantino1, Annalisa Astolfi9, Maria Abbondanza Pantaleo3. 1. "Giorgio Prodi" Cancer Research Center, University of Bologna, 40138 Bologna, Italy. 2. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy. 3. Division of Oncology, IRCCS-Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy. 4. Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori "Dino Amadori" (IRST), 47014 Meldola, Italy. 5. Pathology Unit, IRCCS-Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy. 6. Laboratory of Oncologic Molecular Pathology, IRCCS-Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy. 7. Radiology Unit, IRCCS-Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy. 8. Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy. 9. Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
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.
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.
Authors: Li-Ching Lin; Wen-Kuan Huang; Chueh-Chuan Yen; Ching-Yao Yang; Meng-Ta Sung; Natalie S.M. Wong; Daniel T T Chua; Sarah W M Lee; Jen-Shi Chen; Chun-Nan Yeh Journal: Front Oncol Date: 2022-06-29 Impact factor: 5.738