胃と腸39巻4号

2004年04月発行

特集 消化管の粘膜下腫瘍 2004 総論 2. 狭義のGISTの分子生物学的特徴

狭義のGISTの分子生物学的特徴

著者： 佐久間裕司¹ 櫻井信司¹

所属機関： ¹自治医科大学病理学教室

ページ範囲：P.405 - P.412

要旨　gastrointestinal stromal tumor（GIST）の大多数には，c-kit遺伝子に機能獲得性突然変異が認められ，それがGIST発生に必須の役割を果たしていると考えられる．しかし，c-kit変異のみでGISTが発生しうるのかどうかは定かではない．GISTでは悪性度が増すほど，染色体レベルの異常が増えることが示されており，その発生，悪性化にc-kit以外の遺伝子異常の関与も疑われる．一部のc-kit遺伝子変異陰性GISTには血小板由来増殖因子受容体α（PDGFRα）遺伝子に機能獲得性突然変異が認められる．また，c-kit，PDGFRα遺伝子変異の乏しい神経線維腫症1型に合併する多発性GISTも報告されている．分子標的治療の適切な選択を行うためにも，さらなるGISTの発生，悪性化に関する分子メカニズムの解明が必要である．

参考文献

1）Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279 : 577-580, 1998

2）Ashman LK. The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol 31 : 1037-1051,1999

3）Sakurai S, Fukasawa T, Chong JM, et al. Embryonic form of smooth muscle myosin heavy chain (SMemb/MHC-B) in gastrointestinal stromal tumors and interstitial cells of Cajal. Am J Pathol 154 : 23-28, 1999

4）Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61 : 8118-8121, 2001

5）Miettinen M, El-Rifai W, Sobin LH, et al. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors : A review. Hum Pathol 33 : 478-483, 2002

6）Sakurai S, Fukasawa T, Chong JM, et al. C-kit gene abnormalities in gastrointestinal stromal tumors (tumorsof interstitial cells of Cajal). Jpn J Cancer Res 90 :1321-1328, 1999

7）Sakurai S, Oguni S, Hironaka M, et al. Mutations in c-kit gene exons 9 and 13 in gastrointestinal stromal tumors among Japanese. Jpn J Cancer Res 92 : 494-498, 2001

8）Corless CL, McGreevey L, Haley A, et al. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 160 : 1567-1572, 2002

9）Kitamura Y, Hirota S, Nishida T. Gastrointestinal stromal tumors (GIST) : A model for molecule-based diagnosis and treatment of solid tumors. Cancer Sci 94 : 315-320, 2003

10）Longley BJ Jr, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci USA 96 : 1609-1614, 1999

11）Sakuma Y, Sakurai S, Oguni S, et al. Alterations of the c-kit gene in testicular germ cell tumors. Cancer Sci 94 : 486-491, 2003

12）Sommer G, Agosti V, Ehlers I, et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc Natl Acad Sci USA 100 : 6706-6711, 2003

13）Heinrich MC, Corless CL, Duensing A, et al. PDGFR α activating mutations in gastrointestinal stromal tumors. Science 299 : 708-710, 2003

14）Hirota S, Ohashi A, Nishida T, et al. Gain-of-function mutations of platelet-derived growth factor receptor α gene in gastrointestinal stromal tumors. Gastroenterology 125 : 660-667, 2003

15）Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 23 : 4342-4349, 2003

16）Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib in advanced gastrointestinal stromal tumors. N Engl J Med 347 : 472-480,2002

17）Ishida T, Wada I, Horiuchi H, et al. Multiple small intestinal stromal tumors with skeinoid fibers in association with neurofibromatosis 1 (von Recklinghausen sdisease). Pathol Int 46 : 689-695, 1996

18）Kinoshita K, Hirota S, Isozaki K, et al. Absence of c-kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patients. J Pathol 202 : 80-85, 2004

19）El-Rifai W, Sarlomo-Rikala M, Andesson LC, et al. DNA sequence copy number changes in gastrointestinal stromal tumors. Cancer Res 60 : 3899-3903, 2000

alterations in gastrointestinal stromal tumors. J Clin Oncol 21 : 1688-1697, 2003

21）Fukasawa T, Chong JM, Sakurai S, et al. Allelic loss of 14q and 22q, NF2 mutation, and genetic instability occur independently of c-kit mutation in gastrointestinal stromal tumor. Jpn J Cancer Res 91 : 1241-1249, 2000

22）Sakurai S, Fukayama M, Kaizaki Y, et al. Telomerase activity in gastrointestinal stromal tumors. Cancer 83 : 2060-2066, 1998