Molecular and functional characterization of a new 3′ end KIT juxtamembrane deletion in a duodenal GIST treated with neoadjuvant Imatinib

// Vittorio Perfetti 1, * , Erik Laurini 2, * , Suzana Aulic 2 , Maurizio Fermeglia 2 , Roberta Riboni 3 , Marco Lucioni 3 , Elena Dallera 3 , Sara Delfanti 4 , Luigi Pugliese 5 , Francesco Saverio Latteri 6 , Andrea Pietrabissa 5 and Sabrina Pricl 2 1 Internal Medicine, Ospedale SS Annunziata-ASST Pavia and Department of Molecular Medicine University of Pavia, 27100 Pavia, Italy 2 Molecular Simulation Engineering (MOSE) Laboratory, Pharmaceutical and Molecular Biology Division, DEA, University of Trieste, 34127 Trieste, Italy 3 Department of Molecular Medicine and Anatomic Pathology Section, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy 4 Department of Oncology and Hematology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy 5 Department of Surgery, General Surgery II, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy 6 General Surgery, Ospedale Cannizzaro, 95126 Catania, Italy * These authors contributed equally to this work and are First co-authors Correspondence to: Sabrina Pricl, email: sabrina.pricl@dia.units.it Keywords: KIT, GIST, novel deletion mutation, Imatinib, neoadjuvant treatment Received: April 27, 2017      Accepted: June 28, 2017      Published: July 18, 2017 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.