Influence of various types of receptor tyrosine kinase gene mutations in pathogenesis of GISTs

• Project/Area Number: 23390094
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Hyogo Medical University
• Principal Investigator: HIROTA Seiichi 兵庫医科大学, 医学部, 教授 (50218856)
• Co-Investigator(Kenkyū-buntansha): TSUKAMOTO Yoshitane 兵庫医科大学, 医学部, 准教授 (70461085)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,760,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥4,560,000); Fiscal Year 2013: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2012: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2011: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: c-kit遺伝子 / キナーゼドメインII / 遺伝子改変マウス / シグナル系 / imatinib / nilotinib / GIST多発家系 / 細胞外領域 / GIST / 家族性GIST / ノックインマウス / シグナル伝達物質 / 消化管間質腫瘍 / チロシンキナーゼ / 遺伝子変異 / 培養細胞 / 機能獲得性突然変異 / 傍細胞膜領域 / シグナル伝達

Research Abstract

Signal transduction system activated in immortalized mast cell line which is derived from cultured mast cells of knock-in mice with germline homozygous mutation at kinase domain II was different from that in cultured mast cells of knock-in mice with germline homozygous mutation. The immortalized mast cell line had an additional mutation in the c-kit gene.
Activation of newly found juxtamembrane domain germline c-kit gene gain-of-function mutation in familial GISTs was effectively inhibited by imatinib and nilotinib. We also found that activation of newly found extracellular domain c-kit gene mutation in sporadic GISTs is effectively inhibited by imatinib and nilotinib, compared to that of conventional extracellular domain c-kit gene mutation.

Research Products

• [Journal Article] Re-appraisal of risk classifications for primary gastrointestinal stromal tumors (GIST) after complete resection : indications for adjuvant therapy (2014)
  • Author(s): Yanagimoto Y, Takahashi T, Muguruma K, Toyokawa T, Kusanagi H, Omori T, Masuzawa T, Tanaka K, Hirota S, Nishida T
  • Journal Title: Gastric cancer Volume: (In press) Issue: 2 Pages: 426-433
  • DOI: 10.1007/s10120-014-0386-7
  • Year and Date: 2014-05-23
  • Peer Reviewed
• [Journal Article] A case of diffuse infiltrating gastrointestinal stromal tumor of sigmoid colon with perforation (2014)
  • Author(s): Yamashita D, Usami Y, Toyosawa S, Hirota S, Imai Y
  • Journal Title: Pathol Int Volume: 64 Issue: 1 Pages: 34-38
  • DOI: 10.1111/pin.12124
  • Peer Reviewed
• [Journal Article] Multiple gastrointestinal stromal tumors with novel germline c-kit gene mutation, K642T, at exon 13 (2014)
  • Author(s): Yamanoi K, Higuchi K, Kishimoto H, Nishida Y, Nakamura M, Sudoh M, Hirota S
  • Journal Title: Human Pathol Volume: 45 Issue: 4 Pages: 884-888
  • DOI: 10.1016/j.humpath.2013.11.009
  • Peer Reviewed
• [Journal Article] Subgroups of patients with very large gastrointestinal stromal tumors with distinct prognoses : a multicenter study (2014)
  • Author(s): Wada N, Kurokawa Y, Nishida T, Takahashi T, Toyokawa T, Kusanagi H, Hirota S, Tsujinaka T, Mori M, Doki Y
  • Journal Title: J Surg Oncol Volume: 109 Issue: 2 Pages: 67-70
  • DOI: 10.1002/jso.23471
  • Peer Reviewed
• [Journal Article] Adjuvant therapy with imatinib mesylate after resection of primary high-risk gastrointestinal stromal tumors in Japanese patients (2013)
  • Author(s): Kanda T, Nishida T, Wada N, Kobayashi O, Yamamoto M, Sawaki A, Boku N, Koseki M, Doi T, Toh Y, Kakeji Y, Sugiyama T, Komatsu Y, Kikuchi S, Ogoshi K, Katai H, Miyachi K, Hirota S, Ohtsu A
  • Journal Title: Int J Clin Oncol Volume: 18 Issue: 1 Pages: 38-45
  • DOI: 10.1007/s10147-011-0339-7
  • NAID: 10031176233
  • Peer Reviewed
• [Journal Article] Imatinib therapy for a patient with metastasis of colonic gastrointestinal stromal tumor : Report of a case (2013)
  • Author(s): Okamura T, Kanda T, Hirota S, Nishimura A, Kawahara M, Nikkuni K
  • Journal Title: Clin J Gastroenterol Volume: 6 Issue: 2 Pages: 116-121
  • DOI: 10.1007/s12328-013-0365-2
  • Peer Reviewed
• [Journal Article] Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503 (2013)
  • Author(s): Liu N-N, Ohkouchi M, Hashikura Y, Kajimoto N, Matsuda I, Isozaki K, Toh Y, Takahashi T, Nishida T, Hirota S
  • Journal Title: Lab Invest Volume: 93 Issue: 5 Pages: 502-507
  • DOI: 10.1038/labinvest.2013.43
  • Peer Reviewed
• [Journal Article] Clinical significance of surgery for gastric submucosal tumors with size enlargement during watchful waiting period (2013)
  • Author(s): Miyazaki Y, Nakajima K, Kurokawa Y, Takahashi T, Takiguchi S, Miyata H, Yamasaki M, Hirota S, Nishida T, Mori M, Doki Y
  • Journal Title: Eur J Cancer Volume: 49 Issue: 12 Pages: 2681-2688
  • DOI: 10.1016/j.ejca.2013.04.006
  • Peer Reviewed
• [Journal Article] Characterization of novel germline c-kit gene mutation, KIT-Tyr553Cys, observed in a family with multiple gastrointestinal stromal tumors (2012)
  • Author(s): Nakai M, Hashikura Y, Ohkouchi M, Yamamura M, Akiyama T, Shiba K, Kajimoto N, Tsukamoto Y, Hao H, Isozaki K, Hirai T, Hirota S
  • Journal Title: Lab Invest Volume: 92 Issue: 3 Pages: 451-457
  • DOI: 10.1038/labinvest.2011.165
  • Peer Reviewed
• [Journal Article] Extra-gastrointestinal stromal tumor of the pelvic cavity : case report (2012)
  • Author(s): Hirano H, Yoshida T, Yoshimura H, Fukuoka M, Ohmura N, Nishizawa Y, Tachibana S, Hirota S, Zozumi M, Nishigami T
  • Journal Title: Med Mol Morphol Volume: 45 Issue: 3 Pages: 173-177
  • DOI: 10.1007/s00795-011-0568-x
  • NAID: 10031073970
  • Peer Reviewed
• [Journal Article] Greater omentum gastrointestinal stromal tumor with PDGFRA-mutation and hemoperitoneum (2012)
  • Author(s): Murayama Y, Yamamoto M, Iwasaki R, Miyazaki T, Saji Y, Doi Y, Fukuda H, Hirota S, Hiratsuka M
  • Journal Title: World J Gastroint Oncol Volume: 4 Issue: 5 Pages: 119-124
  • DOI: 10.4251/wjgo.v4.i5.119
  • Peer Reviewed
• [Journal Article] Prospective observational study of imatinib therapy in Japanese patients with advanced gastrointestinal stromal tumors : long-term follow-up and second malignancy (2012)
  • Author(s): Kanda T, Ishikawa T, Hirota S, Yajima K, Kosugi S, Ohashi M, Suzuki S, Mashima Y, Ajioka Y, Hatakeyama K
  • Journal Title: Jpn J Clin Oncol Volume: 42 Issue: 7 Pages: 578-585
  • DOI: 10.1093/jjco/hys056
  • Peer Reviewed
• [Journal Article] Good clinical response to imatinib mesylate in atypical thymic carcinoid with KIT overexpression (2011)
  • Author(s): Hamada S, Masago K, Mio T, Hirota S, Mishima M
  • Journal Title: J Clin Oncol Volume: 29 Issue: 1 Pages: e9-e10
  • DOI: 10.1200/jco.2010.30.2455
  • Peer Reviewed
• [Journal Article] Secondary resistance to imatinib mesylate 70 months after innitiation of therapy in a patient with a metastatic gastric gastrointestinal stromal tumor (2011)
  • Author(s): Tatsuda K, Kanda T, Ishikawa T, Hirota S, 他
  • Journal Title: Clin J Gastroenterol Volume: 4 Issue: 4 Pages: 218-222
  • DOI: 10.1007/s12328-011-0234-9
  • Peer Reviewed
• [Journal Article] Familial gastrointestinal stromal tumor with germ line mutation of the juxtamembrane domain of the KIT gene observed in relatively young women (2011)
  • Author(s): Kuroda N, Tanida N, Hirota S, Daum O, Hes O, Michal M, Lee G-H
  • Journal Title: Ann Diag Pathol Volume: 15 Issue: 5 Pages: 358-361
  • DOI: 10.1016/j.anndiagpath.2010.05.003
  • Peer Reviewed
• [Journal Article] Adjuvant therapy with imatinib mesylate after resection of primary high-risk gastrointestinal stromal tumors in Japanese patients
  • Author(s): Kanda T., et al
  • Journal Title: Int J Clin Oncol Volume: (In press)
  • Peer Reviewed
• [Journal Article] The greater omentum gastrointestinal stromal tumor (GIST) with PDGFRA-mutation with hemoperitoneum
  • Author(s): Murayama Y., et al
  • Journal Title: World J Gastroint Oncol Volume: (In press)
  • Peer Reviewed
• [Journal Article] Prospective observational study of imatinib therapy in Japanese patients with advanced gastrointestinal stromal tumors : long-term follow-up and second malignancy
  • Author(s): Kanda T., et al
  • Journal Title: JPN J Clin Oncol Volume: (In press)
  • Peer Reviewed
• [Presentation] 初診時同時多発肝転移が見られ, 約9年の経過の後死亡した胃原発 GIST の一剖検例 (2014)
  • Author(s): 伊藤周明, 小賀厚徳, 飯田武, 近藤智子, 廣田誠一, 伊藤浩史
  • Organizer: 第103回病理学会総会(示説)
  • Place of Presentation: 広島
  • Year and Date: 2014-04-26
• [Presentation] GIST の起源と病態の解明.シンポジウム1(腫瘍病理学の真髄) (2014)
  • Author(s): 廣田誠一
  • Organizer: 第103回病理学会総会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24
• [Presentation] KIT-Dup-Ser501Ala502 変異を持つ GISTの臨床病理学的特徴と変異分子の生物学的特徴の検討 (2014)
  • Author(s): 劉寧寧, 井出良浩, 梶本仙子, 木村尚美, 松田育雄, 廣田誠一
  • Organizer: 第103回病理学会総会(示説)
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24
• [Presentation] KIT-Dup-Ser501Ala502変異を持つGISTの臨床病理学的特徴と変異分子の生物学的特徴の検討 (2014)
  • Author(s): 劉寧寧，井出良浩，梶本仙子，木村尚美，松田育雄，廣田誠一
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島
• [Presentation] GIST におけるグローバルな DNA メチル化の解析 (2013)
  • Author(s): 松田 育雄, 廣田 誠一
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2013-06-08
• [Presentation] 転移・再発性 GIST におけるイマチニブ治療と二次耐性-分子標的治療のモデル疾患として (2013)
  • Author(s): 神田達夫, 石川卓, 廣田誠一
  • Organizer: 第54回日本臨床細胞学会, シンポジウム
  • Place of Presentation: 東京
• [Presentation] 類 上 皮 型gastrointestinal stromal tumor (GIST)の細胞像 (2013)
  • Author(s): 佐藤元, 榎本利香, 織田みほ, 岡村義弘, 鳥居良貴, 中井真由美, 松田育雄, 塚本吉 胤 , 廣 田 誠 一
  • Organizer: 第54回日本臨床細胞学会総会
  • Place of Presentation: 東京
• [Presentation] GISTにおけるグローバルなDNAメチル化の解析 (2013)
  • Author(s): 松田 育雄, 廣田 誠一
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] GIST の分子標的治療と病理診断.系統的・剖検病理診断講習(分子標的療法と病理診断) (2012)
  • Author(s): 廣田誠一
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-28
• [Presentation] GIST における転写因子 ETV1 の発現について (2012)
  • Author(s): 松田育雄, 廣田誠一
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-26
• [Presentation] Germline に新たな c-kit 遺伝子変異が認められた多発 GIST の一例 (2012)
  • Author(s): 山ノ井一裕, 岸本浩史, 西田保則, 中村将人, 須藤素弘, 廣田誠一, 樋口佳代子
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-26
• [Presentation] 病理学と GIST 研究.病理学入門シリーズ 1(癌病理学) (2012)
  • Author(s): 廣田誠一
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-26
• [Presentation] 病理学とGIST研究 (2012)
  • Author(s): 廣田誠一
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] GISTの分子標的治療と病理診断 (2012)
  • Author(s): 廣田誠一
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] Pathology of gastrointestinal stromal tumours. (2012)
  • Author(s): Hirota S
  • Organizer: 202th Scientific Meeting of the Pathological Society of Great Britain & Ireland
  • Place of Presentation: Sheffield, Great Britain
  • Invited
• [Presentation] GISTの病態解明から分子標的治療への展開を振り返る-Patient Zeroから10年を迎えて- (2011)
  • Author(s): 廣田誠一
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2011-04-29