Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express the receptor tyrosine kinase KIT, and the majority of GISTs present KIT gain-of-function mutations that cluster in the 5′ end of the receptor juxtamembrane domain. On the other hand, little information is known about GISTs carrying mutations in the 3′ end of the KIT juxtamembrane domain. Here we report and discuss a clinical case of localized duodenal GIST whose molecular characterization revealed the presence of a new 21 nucleotide/7 amino acid deletion in the 3′ end of KIT juxtamembrane domain (Δ574–580). The patient was treated with Imatinib at standard regimen dose (400 mg/day), and responded well as the original tumor mass reduced, ultimately allowing conservative surgery. In line with these clinical evidences computer simulations, biophysical techniques and in vitro experiments demonstrated that the receptor tyrosine kinase KIT carrying the Δ574–580 mutation displays constitutive phosphorylation, which can be switched-off upon Imatinib treatment. In addition, results from this study showed that a clinical useful procedure, neoadjuvant treatment, can occasionally be of value for the understanding of the molecular pathogenesis of GIST.

Highlights

  • Gastrointestinal stromal tumors (GISTs) are a relatively rare entity, accounting for less than 1% of GI tumors; they represent the most common mesenchymal tumors of the GI tract

  • In line with these clinical evidences computer simulations, biophysical techniques and in vitro experiments demonstrated that the receptor tyrosine kinase KIT carrying the Δ574–580 mutation displays constitutive phosphorylation, which can be switchedoff upon Imatinib treatment

  • Gastrointestinal stromal tumors are not exception to this, in that the majority of GISTs patients present primary activating mutations in the gene encoding the mast/stem cell growth factor receptor KIT, a type III receptor tyrosine kinase (RTK) that plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis

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Summary

Introduction

Gastrointestinal stromal tumors (GISTs) are a relatively rare entity, accounting for less than 1% of GI tumors; they represent the most common mesenchymal tumors of the GI tract. The vast majority of KIT mutations (60–70%) are in-frame deletions (other include missense mutations (20–30%) and internal tandem duplications) clustered in the 5′ end of KIT juxtamembrane (KIT-JM) domain (exon 11) between Q550 and E561. Alterations in the 3′ end distal part of KIT-JM are rarely reported, and these include missense point mutations in codon L576, in-frame deletions, and rare internal tandem duplications of 1 up to more than 20 codons that are more often observed in gastric GISTs and associated with a favorable outcome [4]. The remaining cases (12–15%) lack KIT and PDGFRA mutations (KIT and PDGFRA wild-type GISTs), but these may include BRAF mutations (3%), loss of function of succinate dehydrogenase (SDH) complex (3%), and NF-1 mutations [9]

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