Abstract
Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies1,2,3,4,5. However, this proposition is complicated by spatial and temporal heterogeneity6,7,8,9,10,11,12,13,14. 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.
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Acknowledgements
This work was supported by a grant of the Korea Health Technology R&D project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418). R.R. acknowledges funding from the NIH (U54 CA193313, R01 CA185486, R01 CA179044). J.W. is supported by Precision Medicine Fellowship (UL1 TR000040). E.L. is supported by NIH (F99 CA212478) and Cancer Biology Training Program (T32 CA09503).
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J.-K.L., J.W., J.K.S., and E.L. are co-first authors. J.-K.L., J.W., J.K.S., and E.L. performed the majority of experiments and analyses. W.-Y.P., H.-O.L., K.-T.K., P.G.C., and P.v.N. performed experiments and analyses for the single-cell transcriptome. D.S.R., Z.L., A.B., A.C., Y.J.S., and S.S. conducted several experiments and analyses. D.-H.N., D.-S.K., H.J.S., C.-K.P., and J.-I.L. provided surgical specimens. S.W.J., S.W.C., and J.K. helped interpret clinical data. W.-Y.P., I.-H.L., Y. J.S., J.-M.O., and H.J.K. organized and processed specimens and genome data. J.-K.L., J.W., J.K.S., E.L., and P.G.C. wrote the manuscript with feedback from R.R., A.I., and D.-H.N. D.-H.N. and R.R. designed and supervised the entire project.
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Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–17, Supplementary Tables 3–6 and Supplementary Note (PDF 4975 kb)
Supplementary Table 1
Descriptive characteristics of multisector/longitudinal samples from the Samsung Medical Center (SMC) and TCGA cohorts. (XLSX 25 kb)
Supplementary Table 2
Somatic mutations and estimation of cancer cell frequency. (XLSX 4214 kb)
Supplementary Video 1
The truncal hypothesis. Illustrative Flash video for conceptual suggestion of the optimal therapeutic strategy for abolishing maximal tumor burden and preventing possible recurrence using multisector genomic information. (WMV 6697 kb)
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Lee, JK., Wang, J., Sa, J. et al. Spatiotemporal genomic architecture informs precision oncology in glioblastoma. Nat Genet 49, 594–599 (2017). https://doi.org/10.1038/ng.3806
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DOI: https://doi.org/10.1038/ng.3806
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