1998 Fiscal Year Final Research Report Summary
Role of the c-kit tyrosine kinase in the genesis of gastrointestinal stromal tumors.
| Project/Area Number |
09671305
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Osaka University |
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Principal Investigator |
NISHIDA Toshirou Osaka University Medical School, Assistant Professor, 医学部, 助手 (40263264)
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| Co-Investigator(Kenkyū-buntansha) |
HIROTA Seiichi Osaka University Medical School, Associate Professor, 医学部, 助教授 (50218856)
UCHIYAMA Yasuo Osaka University Medical School, Professor, 医学部, 教授 (10049091)
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| Project Period (FY) |
1997 – 1998
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| Keywords | gastrointestinal tract / proto-oncogene / gain-of-function mutation / stromal tumors / recurrence / prognosis / c-kit |
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| Research Abstract |
The etiology and cellular origin of gastrointestinal stroma tumors (GISTs) are unknown.Sequencing of c-kil complementary DNA from five GISTs revealed mutations in the juxtamembrane domain.All corresponding mutant KIT proteins were constitutively activated without KIT ligand, the stem cell factor (SCF).Stable transfection of the mutant c-kil complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells.Because the development of the interstitial cells of Cajal (ICCs) is dependent on the SCF-KlT interaction and because both GISTs and ICCs express KIT and CD 34, GISTs may originate from the ICCs.We have found a family with multiple GISTs, of which many family members suffered from multiple GISTs and related symptoms.The family members with multiple GISTs showed the same c-kil mutation in the juxtamembrance domain.The c-kil mutation of this family was detected not only in GISTs but also in leukocytes, thus, familial GISTs appeared to be a cancer syndrome.Next we examined the correlation between the presence of c-kil mutation and the prognosis of GISTs.One hundred and twenty four patients with GIST were analyzed.Most GISTs (89%) express the c-kil protein, and missense mutations of exon 11 were found in 71 out of 124 GISTs.These 71 mutation-positive (+) GISTs were larger in size and invaded more frequently to adjacent tissues compared with the 53 mutation-negative (-) GISTs.Histologically, the mutation (+) GISTs showed higher mitotic figures and more necrosis and hemorrhage.The patients with mutation (+) GISTs showed more frequent recurrences and higher mortality than those with mutation (-) GISTs.The c-kil mutation was an independent prognostic factor for overall and cause-specific survival of the patients with GISTs.
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