Analysis of KIT Mutations in Sporadic and Familial Gastrointestinal Stromal Tumors: Therapeutic Implications through Protein Modeling

• Chi Tarn

  1Medical Oncology, Departments of

• Erin Merkel

  1Medical Oncology, Departments of

• Adrian A. Canutescu

  2Basic Sciences, and

• Wei Shen

  1Medical Oncology, Departments of

• Yuliya Skorobogatko

  1Medical Oncology, Departments of

• Martin J. Heslin

  4Department of Surgery, University of Alabama at Birmingham, Alabama; and

• Burton Eisenberg

  5Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

• Ruth Birbe

  3Pathology, Fox Case Cancer Center, Philadelphia, Pennsylvania;

• Arthur Patchefsky

  3Pathology, Fox Case Cancer Center, Philadelphia, Pennsylvania;

• Roland Dunbrack

  2Basic Sciences, and

• J. Pablo Arnoletti

  4Department of Surgery, University of Alabama at Birmingham, Alabama; and

• Margaret von Mehren

  1Medical Oncology, Departments of

• Andrew K. Godwin

  1Medical Oncology, Departments of

抄録

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 protein 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.

収録刊行物

• Clinical Cancer Research

  Clinical Cancer Research 11 (10), 3668-3677, 2005-05-15

  American Association for Cancer Research (AACR)

キーワード

• Cancer Research
• Oncology

詳細情報

• CRID: 1363670320709949056
• NII論文ID: 30018691273
• DOI: 10.1158/1078-0432.ccr-04-2515
• ISSN: 15573265
• ISSN: 10780432
• Web Site: https://aacrjournals.org/clincancerres/article-pdf/11/10/3668/1920486/3668-3677.pdf
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