2004 Fiscal Year Final Research Report Summary
Analysis of familial and multiple GIST
| Project/Area Number |
14370076
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Experimental pathology
|
|---|
| Research Institution | Hyogo College of Medicine (2004)
Osaka University (2002-2003) |
|---|
Principal Investigator |
HIROTA Seiichi Hyogo College of Medicine, Faculty of Medicine, Professor, 医学部, 教授 (50218856)
|
|---|
| Project Period (FY) |
2002 – 2004
|
| Keywords | GIST / Familial and multiple GISTs / model mouse / knock-in-mouse / Imatinib / c-kit gene / PDGFR alpha / von Recklinghausen disease |
|---|
| Research Abstract |
We found a patient with multiple GISTs(gastrointestinal stromal tumors), and examined his family to clarify whether the cause of multiple GISTs might be derived from germline c-kit mutation. Some members of his family similarly had multiple GISTs, and they had c-kit gene mutation at tyrosine kinase II domain. Proliferation of interstitial cells of Cajal(ICCs) was also seen in the patients as in the cases reported previously. The mutation was proved to be gain-of-function mutation, and is considered to be a cause of multiple GISTs in this family. This family is the first case with germline c-kit gene mutalion at at tyrosine kinase II domain.
We further examined the clonality of diffuse proliferation of ICCs in familial GIST patients. The proliferative lesion showed polyclonal nature while each GIST demonstrated to be monoclonal. We also showed that KIT activation by tyrosine kinase II domain mutation was not effectively inhibited by a selective tyrosine kinase inhibitor, Imatinib. The downstream molecules of KIT signal transduction were not also fully inhibited by Imatinib.
We investigated the cause of GISTs without c-kit gene mutation. Approximately half of GISTs without c-kit gene mutation had PDGFR alpha gene mutation. Two types of PDGFR alpha gene mutation were seen, and KIT activation by the juxtamembrane domain mutation was effectively inhibited by Imatinib but that by the tyrosine kinase II domain mutation was not. We demonstrated that regrowth of GISTs during the Imatinib treatment (development of resistant clone) was caused by an additional c-kit gene mutation to original c-kit gene mutation. Moreover, we showed that GISTs from neurofibromatosis type1 patients did not have any c-kit gene mutation.
|
-
-
-
-
-
-
-
-
-
-
[Journal Article] Endoscopic ultrasonography guided fine needle aspiration biopsy in follow-up patients with gastrointestinal stromal tumors.2003
Author(s)
Kinoshita K, Isozaki K, Tsutsui S, Kitamura S, Hiraoka S, Watabe K, Nakahara M, Nagasawa Y, Kiyohara T, Miyazaki Y, Hirota S, Nishida T, Shinomura Y, Matsuzawa Y
-
Journal Title
Eur J Gastroenterol Hepatol 15
Pages: 1189-1193
Description
「研究成果報告書概要(欧文)」より
-
-
[Journal Article] C-kit gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors.2003
Author(s)
Kinoshita K, Isozaki K, Hirota S, Nishida T, Chen H, Nakahara M, Nagasawa Y, Ohashi A, Shinomura Y, Kitamura Y, Matsuzawa Y
-
Journal Title
J Gastroenterol Hepatol 18
Pages: 147-151
Description
「研究成果報告書概要(欧文)」より
-
-
-
[Journal Article] Polyclonal nature of diffuse proliferation of interstitial cells of Cajal in patients with familial and multiple gastrointestinal stromal tumours.2002
Author(s)
Chen H, Hirota S, Isozaki K, Sun H, Ohashi A, Kinoshita K, O'Brien P, Kapusta L, Dardick I, Obayashi T, Okazaki T, Shinomura Y, Matsuzawa Y, Kitamura Y
-
Journal Title
Description
「研究成果報告書概要(欧文)」より
-
[Journal Article] Familial gastrointestinial stromal tumors associated with dysphagia and novel type germline mutation of KIT gene.2002
Author(s)
Hirota S, Nishida T, Isozaki K, Taniguchi M, Nishikawa K, Ohashi A, Takabayashi A, Obayashi T, Okuno T, Kinoshita K, Chen H, Shinomura Y, Kitamura Y
-
Journal Title
Gastroenterology 122
Pages: 1493-1499
Description
「研究成果報告書概要(欧文)」より
-
