Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

Abstract

Succinate dehydrogenase-deficient gastrointestinal stromal tumors (GISTs) demonstrate unique pathological and clinical features, including the absence of activating mutations of KIT and PDGFRA, and primary resistance to imatinib. They arise exclusively in the stomach and account for 5-7.5% of all adult stomach GISTs and the great majority of these tumors in childhood. Insulin-like growth factor 1 receptor (IGF1R) overexpression has been associated with wild-type and pediatric GISTs. We propose that IGF1R overexpression is a feature of succinate dehydrogenase-deficient GISTs as a group. We assessed succinate dehydrogenase complex subunit B (SDHB) and IGF1R expression by immunohistochemistry in eight known succinate dehydrogenase-deficient GISTs, three GISTs arising in the setting of neurofibromatosis type 1 syndrome and 40 unselected GISTs. Selected KIT and PDGFRA exons were amplified and sequenced from formalin-fixed paraffin-embedded tumor samples. All eight succinate dehydrogenase-deficient tumors were wild-type for KIT and PDGFRA, succinate dehydrogenase B negative and demonstrated IGF1R overexpression. The three neurofibromatosis-related tumors were succinate dehydrogenase B positive and IGF1R negative. Of the 40 unselected upper GISTs, five were wild-type for KIT and PDGFRA in the selected exons. Two of the wild-type GISTs were succinate dehydrogenase B negative and showed IGF1R overexpression and three were succinate dehydrogenase B positive and IGF1R negative. We conclude that IGF1R overexpression is a feature of succinate dehydrogenase deficient GIST as a group, rather than pediatric or wild-type GIST per se. Therefore, IGF1R inhibition represents a potential rational therapeutic approach in this recently recognized subgroup of GIST.

An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST)

“…In a set of 16 patients with KIT/PDGFRA WT GIST, all eight SDH-deficient KIT/PDGFRA WT tumours were SDHB negative and showed IGF1R overexpression, three NF1-related tumours were SDHB positive and IGF1R negative, and, among five unselected KIT/PDGFRA WT upper GIST, two were SDHB negative and showed IGF1R overexpression and three were SDHB positive and IGF1R negative, suggesting that IGF1R overexpression could be a feature of SDH-deficient GIST as a group, rather than of paediatric or KIT/PDGFRA WT GIST per se 68. In a small series of patients, all four patients with KIT/PDGFRA WT GIST displaying an IGF1R overexpression showed inactivating nonsense or missense SDHA mutations in the coding sequences, compared with respect to either KIT/PDGFRA mutant or KIT/PDGFRA WT GIST without SDH mutations 69.…”

Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST

“…35 Recently, the correlation between the overexpression of the insulinlike growth factor receptor 1 (IGF1R) protein and the status of SDH complex deficiency in KIT/PDGFRA wild-type GIST has been described suggesting that the IGF1R overexpression in this subset of patients may be driven by the loss of function of the SDH complex. [36][37][38][39] Finally, we would like to emphasize that, currently, the majority of KIT/PDGFRA wild-type GIST do not harbor mutations in SDH complex or do not present SDH deficiency, so their molecular background is still unknown. The discovery of the oncogenetic event in this GIST population still represents a great challenge.…”

Small bowel sarcoma: Tumor biology and advances in therapeutics

“…Approximately 85e90% of tumors have KIT (cd117) or PDGFRA mutation. Molecular studies of adult GISTS have confirmed activating mutations in the KIT gene (exons 9,11,13,17) in 90%, most frequently in exon 11. These distinctive KIT mutations have clinical and treatment implications [9].…”

“…Activation of insulin like growth factor1-receptor (IGF1R) signaling is noted in these tumors and may play a role in their pathogenesis (Fig. 3) [12,16,17]. The treatment of GISTs in this entity remains to be defined.…”