7月26日,，Science雜志在線報(bào)道，基因融合易位是引發(fā)部分惡性膠質(zhì)母細(xì)胞瘤的原因，這也許可作為臨床靶向性治療的新依據(jù)。
大腦惡性膠質(zhì)母細(xì)胞瘤（GBM）,，是人類癌癥最致命的類型。本研究發(fā)現(xiàn),，GBM患者的一小部分（3.1％;所檢測(cè)的97個(gè)病例中的3例）具有致癌性染色體易位,，使得成纖維細(xì)胞生長(zhǎng)因子受體（FGFR）（FGFR1或FGFR3）酪氨酸激酶結(jié)構(gòu)域的編碼基因，分別與編碼轉(zhuǎn)化酸性卷曲螺旋（TACC）結(jié)構(gòu)域TACC1或TACC3的基因融合到同一個(gè)閱讀框中,。
當(dāng)引入星形膠質(zhì)細(xì)胞或立體定位轉(zhuǎn)入小鼠大腦時(shí),，F(xiàn)GFR-TACC融合蛋白顯示出致癌活性。此融合蛋白,，定位于有絲分裂紡錘體的兩極,，有構(gòu)成性激酶活性，并可誘導(dǎo)有絲分裂和染色體分離的缺陷,，由此引發(fā)非整倍體。
抑制FGFR激酶活性,，可糾正非整倍體,。口服FGFR的抑制劑可延長(zhǎng)FGFR3-TACC3融合基因引發(fā)的顱內(nèi)膠質(zhì)瘤小鼠的存活期,。FGFR-TACC融合可能成為確定一類將受益于靶向性的FGFR激酶抑制劑治療的GBM患者一個(gè)依據(jù),。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
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Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma
Devendra Singh1,*,Joseph Minhow Chan2,*,Pietro Zoppoli1,*,Francesco Niola1,*,?,Ryan Sullivan1,Angelica Castano1,Eric Minwei Liu2,Jonathan Reichel2,3,Paola Porrati4,Serena Pellegatta4,Kunlong Qiu5,Zhibo Gao5,Michele Ceccarelli6,Riccardo Riccardi7,Daniel J. Brat8,Abhijit Guha9,Ken Aldape10,John G. Golfinos11,David Zagzag11,12,Tom Mikkelsen13,Gaetano Finocchiaro4,Anna Lasorella1,14,15,?,Raul Rabadan2,?,Antonio Iavarone1,15,16,?
The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbor oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition.
