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Nat Genet. 2017 Apr;49(4):594-599. doi: 10.1038/ng.3806. Epub 2017 Mar 6.

Spatiotemporal genomic architecture informs precision oncology in glioblastoma.

Lee JK1,2, Wang J3,4,5, Sa JK1,2,6, Ladewig E3,4, Lee HO7, Lee IH1,2, Kang HJ1,2, Rosenbloom DS3,4, Camara PG3,4, Liu Z3,4, van Nieuwenhuizen P3,4, Jung SW1,2,6, Choi SW1,2,6, Kim J1,2, Chen A3,4, Kim KT7, Shin S1,2,6, Seo YJ1,2, Oh JM1,2, Shin YJ1,2,7, Park CK8, Kong DS2, Seol HJ2, Blumberg A9, Lee JI2, Iavarone A10,11,12, Park WY6,7, Rabadan R3,4, Nam DH1,2,6.

Author information

1
Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
2
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
3
Department of Systems Biology, Columbia University, New York, New York, USA.
4
Department of Biomedical Informatics, Columbia University, New York, New York, USA.
5
Divisions of Life Science and Biomedical Engineering, Hong Kong University of Science and Technology, Hong Kong.
6
Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
7
Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
8
Department of Neurosurgery, College of Medicine, Seoul National University and Seoul National University Hospital, Seoul, Republic of Korea.
9
Department of Mathematics, University of Texas, Austin, Texas, USA.
10
Institute for Cancer Genetics, Columbia University, New York, New York, USA.
11
Department of Neurology, Columbia University, New York, New York, USA.
12
Department of Pathology, Columbia University, New York, New York, USA.

Abstract

Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies. However, this proposition is complicated by spatial and temporal heterogeneity. Here we study genomic and expression profiles across 127 multisector or longitudinal specimens from 52 individuals with glioblastoma (GBM). Using bulk and single-cell data, we find that samples from the same tumor mass share genomic and expression signatures, whereas geographically separated, multifocal tumors and/or long-term recurrent tumors are seeded from different clones. Chemical screening of patient-derived glioma cells (PDCs) shows that therapeutic response is associated with genetic similarity, and multifocal tumors that are enriched with PIK3CA mutations have a heterogeneous drug-response pattern. We show that targeting truncal events is more efficacious than targeting private events in reducing the tumor burden. In summary, this work demonstrates that evolutionary inference from integrated genomic analysis in multisector biopsies can inform targeted therapeutic interventions for patients with GBM.

PMID:
28263318
PMCID:
PMC5627771
DOI:
10.1038/ng.3806
[Indexed for MEDLINE]
Free PMC Article

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