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腾讯登录Science：转化性FGFR-TACC基因融合引发恶性胶质母细胞瘤
| 导读 | 7月26日，<em>Science</em>杂志在线报道，基因融合易位是引发部分恶性胶质母细胞瘤的原因，这也许可作为临床靶向性治疗的新依据。
大脑恶性胶质母细胞瘤（GBM），是人类癌症最致命的类型。本研究发现，GBM患者的一小部分（3.1％;所检测的97个病例中的3例）具有致癌性染色体易位，使得成纤维细胞生长因子受体（FGFR）（FGFR1或FGFR3）酪氨酸激酶结构... |
7月26日，<em>Science</em>杂志在线报道，基因融合易位是引发部分恶性胶质母细胞瘤的原因，这也许可作为临床靶向性治疗的新依据。
大脑恶性胶质母细胞瘤（GBM），是人类癌症最致命的类型。本研究发现，GBM患者的一小部分（3.1％;所检测的97个病例中的3例）具有致癌性染色体易位，使得成纤维细胞生长因子受体（FGFR）（FGFR1或FGFR3）酪氨酸激酶结构域的编码基因，分别与编码转化酸性卷曲螺旋（TACC）结构域TACC1或TACC3的基因融合到同一个阅读框中。
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当引入星形胶质细胞或立体定位转入小鼠大脑时，FGFR-TACC融合蛋白显示出致癌活性。此融合蛋白，定位于有丝分裂纺锤体的两极，有构成性激酶活性，并可诱导有丝分裂和染色体分离的缺陷，由此引发非整倍体。
抑制FGFR激酶活性，可纠正非整倍体。口服FGFR的抑制剂可延长FGFR3-TACC3融合基因引发的颅内胶质瘤小鼠的存活期。FGFR-TACC融合可能成为确定一类将受益于靶向性的FGFR激酶抑制剂治疗的GBM患者一个依据。
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<img src="http://www.bioon.com/biology/UploadFiles/201207/2012072710022616.jpg" alt="" width="113" height="149" border="0" hspace="0" />
<a title="" href="http://dx.doi.org/10.1016/j.cell.2011.10.017" target="_blank">doi:</a><a title="" href="http://www.sciencemag.org/content/early/2012/07/25/science.1220834" target="_blank">10.1016/j.cell.2011.10.017</a>
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<br/><strong>Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma</strong><br/>
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.
<br/>来源：生物谷
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大脑恶性胶质母细胞瘤（GBM），是人类癌症最致命的类型。本研究发现，GBM患者的一小部分（3.1％;所检测的97个病例中的3例）具有致癌性染色体易位，使得成纤维细胞生长因子受体（FGFR）（FGFR1或FGFR3）酪氨酸激酶结构域的编码基因，分别与编码转化酸性卷曲螺旋（TACC）结构域TACC1或TACC3的基因融合到同一个阅读框中。
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当引入星形胶质细胞或立体定位转入小鼠大脑时，FGFR-TACC融合蛋白显示出致癌活性。此融合蛋白，定位于有丝分裂纺锤体的两极，有构成性激酶活性，并可诱导有丝分裂和染色体分离的缺陷，由此引发非整倍体。
抑制FGFR激酶活性，可纠正非整倍体。口服FGFR的抑制剂可延长FGFR3-TACC3融合基因引发的颅内胶质瘤小鼠的存活期。FGFR-TACC融合可能成为确定一类将受益于靶向性的FGFR激酶抑制剂治疗的GBM患者一个依据。
<div id="ztload">
<div>
<div>
<img src="http://www.bioon.com/biology/UploadFiles/201207/2012072710022616.jpg" alt="" width="113" height="149" border="0" hspace="0" />
<a title="" href="http://dx.doi.org/10.1016/j.cell.2011.10.017" target="_blank">doi:</a><a title="" href="http://www.sciencemag.org/content/early/2012/07/25/science.1220834" target="_blank">10.1016/j.cell.2011.10.017</a>
PMC:
PMID:
</div>
<div>
<br/><strong>Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma</strong><br/>
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.
<br/>来源：生物谷
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