TY - JOUR
T1 - Molecular and functional characterization of a new 3' end KIT juxtamembrane deletion in a duodenal GIST treated with neoadjuvant Imatinib
AU - Perfetti, Vittorio
AU - Laurini, Erik
AU - Aulic, Suzana
AU - Fermeglia, Maurizio
AU - Riboni, Roberta
AU - Lucioni, Marco
AU - Dallera, Elena
AU - Delfanti, Sara
AU - Pugliese, Luigi
AU - Latteri, Francesco Saverio
AU - Pietrabissa, Andrea
AU - Pricl, Sabrina
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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 switchedoff 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.
AB - 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 switchedoff 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.
KW - GIST
KW - Imatinib
KW - KIT
KW - Neoadjuvant treatment
KW - Novel deletion mutation
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UR - http://www.scopus.com/inward/citedby.url?scp=85029067907&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.19341
DO - 10.18632/oncotarget.19341
M3 - Article
AN - SCOPUS:85029067907
VL - 8
SP - 56158
EP - 56167
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 34
ER -