Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations

被引：465

作者：

Brastianos, Priscilla K. ^{[1
,2
,3
,4
]}

Horowitz, Peleg M. ^{[3
,4
,5
,6
]}

Santagata, Sandro ^{[3
,7
]}

Jones, Robert T. ^{[1
,8
]}

McKenna, Aaron ^{[4
]}

Getz, Gad ^{[4
]}

Ligon, Keith L. ^{[3
,7
]}

Palescandolo, Emanuele ^{[8
]}

Van Hummelen, Paul ^{[1
,8
]}

Ducar, Matthew D. ^{[1
,8
]}

Raza, Alina ^{[1
,8
]}

Sunkavalli, Ashwini ^{[1
,8
]}

MacConaill, Laura E. ^{[1
,8
]}

Stemmer-Rachamimov, Anat O. ^{[3
,9
]}

Louis, David N. ^{[3
,9
,10
]}

Hahn, William C. ^{[1
,3
,4
,8
]}

Dunn, Ian F. ^{[3
,4
,6
]}

Beroukhim, Rameen ^{[1
,3
,4
,5
,8
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Broad Inst MIT & Harvard, Boston, MA USA

[5] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA

[7] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[8] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[9] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA

[10] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 03期

基金：

美国国家卫生研究院;

关键词：

BASAL-CELL CARCINOMAS; NF2; PATHWAY; CANCER; MEDULLOBLASTOMA; COMPLEXITY; LANDSCAPE; PATTERNS; TUMORS;

D O I：

10.1038/ng.2526

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of all meningiomas(1), but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas had simple genomes, with fewer mutations, rearrangements and copy-number alterations than reported in other tumors in adults. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements, including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers in an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.

引用

页码：285 / 289

页数：5

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