Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma

被引：625

作者：

Singh, Devendra ^{[1
]}

Chan, Joseph Minhow ^{[2
,3
]}

Zoppoli, Pietro ^{[1
]}

Niola, Francesco ^{[1
]}

Sullivan, Ryan ^{[1
]}

Castano, Angelica ^{[1
]}

Liu, Eric Minwei ^{[2
,3
]}

Reichel, Jonathan ^{[2
,3
,4
,5
]}

Porrati, Paola ^{[6
]}

Pellegatta, Serena ^{[6
]}

Qiu, Kunlong ^{[7
]}

Gao, Zhibo ^{[7
]}

Ceccarelli, Michele ^{[8
,9
]}

Riccardi, Riccardo ^{[10
]}

Brat, Daniel J. ^{[11
,12
]}

Guha, Abhijit ^{[13
]}

Aldape, Ken ^{[14
]}

Golfinos, John G. ^{[15
]}

Zagzag, David ^{[15
,16
]}

Mikkelsen, Tom ^{[17
,18
]}

Finocchiaro, Gaetano ^{[6
]}

Lasorella, Anna ^{[1
,19
,20
]}

Rabadan, Raul ^{[2
,3
]}

Iavarone, Antonio ^{[1
,20
,21
]}

机构：

[1] Columbia Univ, Med Ctr, Inst Canc Genet, New York, NY 10027 USA

[2] Columbia Univ, Med Ctr, Dept Biomed Informat, New York, NY USA

[3] Columbia Univ, Med Ctr, Ctr Computat Biol & Bioinformat, New York, NY USA

[4] Cornell Univ, Triinst Program Computat Biol & Med, New York, NY 10021 USA

[5] Weill Cornell Med Coll, New York, NY USA

[6] Carattere Sci Ist Neurol C, Fdn Ist Ricovero & Cura, Milan, Italy

[7] Beijing Genome Inst, Bioinformat Ctr, Shenzhen, Peoples R China

[8] Biogem, Ist Ric Genet Gaetano Salvatore, Ariano Irpino, AV, Italy

[9] Univ Sannio, Dipartimento Sci Biol & Ambientali, Benevento, Italy

[10] Univ Cattolica Sacro Cuore, Dept Pediat Oncol, Rome, Italy

[11] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA

[12] Emory Univ, Sch Med, Dept Lab Med, Atlanta, GA 30322 USA

[13] Univ Toronto, Univ Hlth Network, Toronto Western Hosp, Div Neurosurg, Toronto, ON M5S 1A1, Canada

[14] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[15] NYU, Dept Neurosurg, Langone Med Ctr, New York, NY 10016 USA

[16] NYU, Dept Neuropathol, Langone Med Ctr, New York, NY USA

[17] Henry Ford Hlth Syst, Dept Neurol, Detroit, MI USA

[18] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI USA

[19] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA

[20] Columbia Univ, Med Ctr, Dept Pathol, New York, NY USA

[21] Columbia Univ, Med Ctr, Dept Neurol, New York, NY USA

来源：

SCIENCE | 2012年 / 337卷 / 6099期

关键词：

RECEPTOR TYROSINE KINASE; CHROMOSOMAL INSTABILITY; SELECTIVE INHIBITOR; CANCER; ANEUPLOIDY; FAMILY; DISCOVERY; POTENT;

D O I：

10.1126/science.1220834

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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) harbors 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.

引用

页码：1231 / 1235

页数：5

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