Relation between gain-of-function mutation of c-kit gene and development of GIST

c-kit基因功能获得性突变与GIST发生的关系

• 批准号: 10670204
• 负责人: HIROTA Seiichi
• 金额: $ 2.18万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670204/
• 关键词: c-kit gene; interstitial cells of cajal; GIST; gain-of-function mutation; Prognosis; カハールの介在細胞; がん原遺伝子; c-kit; 間葉細胞腫; 腫瘍発生; 生殖系列

The c-kit protooncogene encodes a receptor tyrosine kinase, KIT receptor and its ligand is stem cell factor, SCF. We found that the gain-of-function mutations at juxtamembrane domain of c-kit gene were frequently observed in gastrointestinal stromal tumors (GISTs). Since GISTs and interstitial cells of Cajal (ICCs) are double-positive for c-kit and CD34, GISTs were considered to originate from ICCs. We also found two families with multiple GISTs. The patients of both families had mutations of c-kit gene not only in tumor tissues but also in normal peripheral blood leukocytes or normal tissues. Therefore, the mutation was determined to be a germline one. The mutations found in the individual families were different each other, but both located in codons 550 to 560 where the mutations of c-kit gene were frequently observed in solitary GISTs. Diffuse hyperplasia of spindle-shaped cells was observed in the myenteric plexus layer of small intestine of the patients.GISTs are the most popular mesenchymal tumor in the gastrointestinal wall, but the differential diagnosis between malignant GISTs and benign GISTs is difficult by conventional histopathological methods. We examined whether the c-kit mutation makes an effect on prognosis of GIST patients. The patients with c-kit mutation showed poorer prognosis than those without c-kit mutation did.

C-kit原癌基因编码一种受体酪氨酸激酶KIT受体，其配体为干细胞因子SCF。我们发现c-kit基因膜旁区域的功能获得突变在胃肠道间质瘤中是常见的。由于GIST和Cajal间质细胞(ICCs)c-kit和CD34双阳性，GIST被认为起源于ICCs。我们还发现了两个有多个GIST的家庭。这两个家系的患者不仅在肿瘤组织中存在c-kit基因突变，而且在正常外周血白细胞或正常组织中也存在c-kit基因突变。因此，该突变被确定为生殖系突变。家系中发现的突变各不相同，但均位于550~560密码子，c-kit基因突变多见于孤立性GIST。患者的小肠肌间神经丛可见弥漫性梭形细胞增生。GIST是胃肠道最常见的间叶性肿瘤，但常规组织病理学方法难以鉴别恶性和良性GIST。我们检测了c-kit突变是否对GIST患者的预后有影响。C-kit基因突变患者预后较无c-kit基因突变患者差。

项目成果

Nishida T: "Familial gastrointestinal steromal tumors with germline mutation of KIT"Nature Genet. 19. 323-324 (1998)

Nishida T：“具有 KIT 种系突变的家族性胃肠道间质肿瘤”Nature Genet。

Kitamura Y: "Molecular pathology of c-kit proto-oncogene and development of gastrointestinal steromal tumors"Ann Chirurg Gynaecol. 87. 282-286 (1998)

Kitamura Y：“c-kit 原癌基因的分子病理学和胃肠道间质瘤的发展”Ann Chirurg Gynaecol。

Kitamura Y, Hirota S, Nishida T.: "Molecular pathology of c-kit proto-oncogene and development of gastrointestinal stromal tumors."Ann Chirurg Gynaecol. 87. 282-286 (1998)

Kitamura Y、Hirota S、Nishida T.：“c-kit 原癌基因的分子病理学和胃肠道间质瘤的发展。”Ann Chirurg Gynaecol。

Nakahara M,Isozaki K,Hirota S et al: "A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors" Gastroenterology. 115. 1090-1095 (1998)

Nakahara M、Isozaki K、Hirota S 等人：“胃肠道间质瘤中 c-kit 基因的新型功能获得性突变”胃肠病学。

Hirota S: "Gain-of-function mutations of c-kit in human gastrointestinal steromal tumors"Science. 279. 577-580 (1998)

Hirota S：“人类胃肠道间质瘤中 c-kit 的功能获得突变”《科学》。