TY - JOUR
T1 - Analysis of KIT mutations in sporadic and familial gastrointestinal stromal tumors
T2 - Therapeutic implications through protein modeling
AU - Tarn, Chi
AU - Merkel, Erin
AU - Canutescu, Adrian A.
AU - Shen, Wei
AU - Skorobogatko, Yuliya
AU - Heslin, Martin J.
AU - Eisenberg, Burton
AU - Birbe, Ruth
AU - Patchefsky, Arthur
AU - Dunbrack, Roland
AU - Arnoletti, J. Pablo
AU - Von Mehren, Margaret
AU - Godwin, Andrew K.
PY - 2005/5/15
Y1 - 2005/5/15
N2 - Purpose: Gastrointestinal stromal tumors (GIST) are characterized by expressing a gain-of-function mutation in KIT, and to a lesser extent, PDGFR. Imatinib mesylate, a tyrosine kinase inhibitor, has activity against GISTs that contain oncogenic mutations of KIT. In this study, KIT and PDGFRα mutation status was analyzed and protein modeling approaches were used to assess the potential effect of KIT mutations in response to imatinib therapy. Experimental Design: Genomic DNA was isolated from GIST tumors. Exons 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRα were evaluated for oncogenic mutations. Protein modeling was used to assess mutations within the juxtamembrane region and the kinase domain of KIT. Results: Mutations in KIT exons 9, 11, and 13 were identified in GISTs with the majority of changes involving the juxtamembrane region of KIT. Molecular modeling indicates that mutations in this region result in disruption of the KIT autoinhibited conformation, and lead to gain-of-function activation of the kinase. Furthermore, a novel germ-line mutation in KIT was identified that is associated with an autosomal dominant predisposition to the development of GIST. Conclusions: We have used proteih modeling and structural analyses to elucidate why patients with GIST tumors containing exon 11 mutations are the most responsive to imatinib mesylate treatment. Importantly, mutations detected in this exon and others displayed constitutive activation of KIT. Furthermore, we have found tumors that are both KIT and PDGFRα mutation negative, suggesting that additional, yet unidentified, abnormalities may contribute to GIST tumorigenesis.
AB - Purpose: Gastrointestinal stromal tumors (GIST) are characterized by expressing a gain-of-function mutation in KIT, and to a lesser extent, PDGFR. Imatinib mesylate, a tyrosine kinase inhibitor, has activity against GISTs that contain oncogenic mutations of KIT. In this study, KIT and PDGFRα mutation status was analyzed and protein modeling approaches were used to assess the potential effect of KIT mutations in response to imatinib therapy. Experimental Design: Genomic DNA was isolated from GIST tumors. Exons 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRα were evaluated for oncogenic mutations. Protein modeling was used to assess mutations within the juxtamembrane region and the kinase domain of KIT. Results: Mutations in KIT exons 9, 11, and 13 were identified in GISTs with the majority of changes involving the juxtamembrane region of KIT. Molecular modeling indicates that mutations in this region result in disruption of the KIT autoinhibited conformation, and lead to gain-of-function activation of the kinase. Furthermore, a novel germ-line mutation in KIT was identified that is associated with an autosomal dominant predisposition to the development of GIST. Conclusions: We have used proteih modeling and structural analyses to elucidate why patients with GIST tumors containing exon 11 mutations are the most responsive to imatinib mesylate treatment. Importantly, mutations detected in this exon and others displayed constitutive activation of KIT. Furthermore, we have found tumors that are both KIT and PDGFRα mutation negative, suggesting that additional, yet unidentified, abnormalities may contribute to GIST tumorigenesis.
KW - Adult
KW - Aged
KW - Amino Acid Sequence
KW - Antineoplastic Agents/pharmacology
KW - Benzamides
KW - Cell Transformation, Neoplastic
KW - Crystallography, X-Ray
KW - DNA Mutational Analysis
KW - DNA, Neoplasm/analysis
KW - Female
KW - Gastrointestinal Stromal Tumors/genetics
KW - Germ-Line Mutation
KW - Humans
KW - Imatinib Mesylate
KW - Male
KW - Middle Aged
KW - Models, Chemical
KW - Molecular Sequence Data
KW - Pedigree
KW - Piperazines/pharmacology
KW - Platelet-Derived Growth Factor/biosynthesis
KW - Protein Conformation
KW - Proto-Oncogene Proteins c-kit/biosynthesis
KW - Pyrimidines/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=21044451716&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000229086600011&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1158/1078-0432.CCR-04-2515
DO - 10.1158/1078-0432.CCR-04-2515
M3 - Article
C2 - 15897563
SN - 1078-0432
VL - 11
SP - 3668
EP - 3677
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -