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Molecular and functional characterization of a new 3' end KIT juxtamembrane deletion in a duodenal GIST treated with
Vittorio Perfetti1, Erik Laurini2, Suzana Aulić2
1Internal Medicine, Ospedale SS Annunziata-ASST Pavia and Department of Molecular Medicine University of Pavia, 27100 Pavia, Italy.
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.
Insights
This study details a duodenal gastrointestinal stromal tumor (GIST) with a novel KIT mutation. Neoadjuvant Imatinib treatment effectively reduced the tumor, enabling surgery and offering insights into GIST molecular pathogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Gastroenterology
Background:
- Gastrointestinal stromal tumors (GISTs) are common mesenchymal tumors.
- Most GISTs have KIT gain-of-function mutations in the 5' juxtamembrane domain.
- Mutations in the 3' KIT juxtamembrane domain are less understood.
Purpose of the Study:
- To report a case of duodenal GIST with a novel 3' KIT juxtamembrane domain mutation (Δ574-580).
- To investigate the molecular behavior of this mutation and its response to Imatinib.
- To explore the utility of neoadjuvant therapy in understanding GIST pathogenesis.
Main Methods:
- Clinical case reporting and molecular characterization of GIST.
- Analysis of KIT juxtamembrane domain mutation (Δ574-580).
- In vitro experiments, computer simulations, and biophysical techniques to study KIT phosphorylation and Imatinib response.
Main Results:
- Identified a new 21 nucleotide/7 amino acid deletion (Δ574-580) in the 3' KIT juxtamembrane domain.
- The Δ574-580 mutation resulted in constitutive KIT phosphorylation.
- Imatinib treatment (400 mg/day) effectively reduced tumor mass and inhibited KIT phosphorylation.
- Conservative surgery was feasible after neoadjuvant Imatinib therapy.
Conclusions:
- The novel Δ574-580 KIT mutation drives GIST development.
- Neoadjuvant Imatinib is effective for GISTs with this mutation, allowing for less invasive surgery.
- This case highlights the importance of molecular characterization and neoadjuvant treatment in managing GISTs.
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