Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors

被引：70

作者：

Ramkissoon, Shakti H. ^{[6
,10
,14
]}

Bandopadhayay, Pratiti ^{[1
,7
,14
]}

Hwang, Jaeho ^{[14
]}

Ramkissoon, Lori A. ^{[6
]}

Greenwald, Noah F. ^{[8
,11
]}

Schumacher, Steven E. ^{[13
]}

O'Rourke, Ryan ^{[8
]}

Pinches, Nathan ^{[7
]}

Ho, Patricia ^{[8
]}

Malkin, Hayley ^{[7
]}

Sinai, Claire ^{[7
]}

Filbin, Mariella ^{[1
,7
,14
]}

Plant, Ashley ^{[1
,7
,14
]}

Bi, Wenya Linda ^{[8
,11
,14
]}

Chang, Michael S. ^{[1
,7
]}

Yang, Edward ^{[3
,14
]}

Wright, Karen D. ^{[1
,7
,14
]}

Manley, Peter E. ^{[1
,7
,14
]}

Ducar, Matthew ^{[9
]}

Alexandrescu, Sanda ^{[2
,14
]}

Lidov, Hart ^{[2
,10
,14
]}

Delalle, Ivana ^{[10
]}

Goumnerova, Liliana C. ^{[1
,4
,7
,14
]}

Church, Alanna J. ^{[2
,14
]}

Janeway, Katherine A. ^{[1
,7
,14
]}

Harris, Marian H. ^{[2
,7
,14
]}

MacConaill, Laura E. ^{[9
,10
,14
]}

Folkerth, Rebecca D. ^{[2
,10
,14
]}

Lindeman, Neal I. ^{[10
,14
]}

Stiles, Charles D. ^{[8
,14
]}

Kieran, Mark W. ^{[1
,7
,14
]}

Ligon, Azra H. ^{[10
,14
]}

Santagata, Sandro ^{[2
,8
,10
,14
]}

Dubuc, Adrian M. ^{[10
,14
]}

Chi, Susan N. ^{[1
,7
,14
]}

Beroukhim, Rameen ^{[5
,8
,12
,13
,14
]}

Ligon, Keith L. ^{[2
,6
,10
,13
,14
]}

机构：

[1] Boston Childrens Hosp, Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA 02115 USA

[2] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

[3] Boston Childrens Hosp, Dept Radiol, Boston, MA USA

[4] Boston Childrens Hosp, Dept Neurosurg, Boston, MA USA

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

[6] Dana Farber Canc Inst, Oncol Pathol, Boston, MA 02115 USA

[7] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

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

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

[10] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[11] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA

[12] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[13] Broad Inst MIT & Harvard, Boston, MA 02115 USA

[14] Harvard Med Sch, Boston, MA 02115 USA

来源：

NEURO-ONCOLOGY | 2017年 / 19卷 / 07期

关键词：

array CGH; brain tumor; clinical sequencing; pediatric neuro-oncology; precision medicine; CENTRAL-NERVOUS-SYSTEM; MOLECULAR CLASSIFICATION; STRUCTURAL VARIATION; MUTATIONS; MEDULLOBLASTOMA; REARRANGEMENTS; GENE;

D O I：

10.1093/neuonc/now294

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background. Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. Methods. Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints. Results. Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. Conclusion. The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.

引用

页码：986 / 996

页数：11

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