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 JK, Wang J, Sa JK, Ladewig E, Lee HO, Lee IH, Kang HJ, Rosenbloom DS, Camara PG, Liu Z, van Nieuwenhuizen P,Jung SW, Choi SW, Kim J, Chen A, Kim KT, Shin S, Seo YJ, Oh JM, Shin YJ, Park CK, Kong DS, Seol HJ, Blumberg A,Lee JI, Iavarone A, Park WY, Rabadan R, Nam DH.
Abstract:
Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies1–5. However, this proposition is complicated by spatial and temporal heterogeneity6–14. 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.
