Spatiotemporal genomic architecture informs precision oncology in glioblastoma

• Published in: Nature genetics Vol. 49; no. 4; pp. 594 - 599
• Main Authors: Lee, Jin-Ku, Wang, Jiguang, Sa, Jason K, Ladewig, Erik, Lee, Hae-Ock, Lee, In-Hee, Kang, Hyun Ju, Rosenbloom, Daniel S, Camara, Pablo G, Liu, Zhaoqi, van Nieuwenhuizen, Patrick, Jung, Sang Won, Choi, Seung Won, Kim, Junhyung, Chen, Andrew, Kim, Kyu-Tae, Shin, Sang, Seo, Yun Jee, Oh, Jin-Mi, Shin, Yong Jae, Park, Chul-Kee, Kong, Doo-Sik, Seol, Ho Jun, Blumberg, Andrew, Lee, Jung-Il, Iavarone, Antonio, Park, Woong-Yang, Rabadan, Raul, Nam, Do-Hyun
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2017; Nature Publishing Group
• Subjects: 45/23; 45/91; 631/114/2785; 631/67/1922; 692/699/67/1059/602; Agriculture; Animal Genetics and Genomics; Biomedicine; Biopsy; Brain Neoplasms - genetics; Cancer; Cancer Research; Care and treatment; Cloning; Development and progression; Experiments; Gene Function; Genetic aspects; Genetic diversity; Genomes; Genomics - methods; Genotypes; Glioblastoma - genetics; Glioblastomas; Health aspects; Human Genetics; Humans; Hypotheses; Innovations; letter; Molecular targeted therapy; Mutation; Mutation - genetics; Neoplasm Recurrence, Local - genetics; Phosphatidylinositol 3-Kinases - genetics; Precision Medicine - methods; Tumors
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3806

Raul Rabadan, Woong-Yang Park, Do-Hyun Nam and colleagues examine the genomic and transcriptomic profiles of tumors from 52 patients with glioblastoma using both bulk and single-cell analyses. They find that tumors that are isolated from distinct locations or at different times are seeded from different clones, suggesting the need for multisector biopsies. Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies 1 , 2 , 3 , 4 , 5 . However, this proposition is complicated by spatial and temporal heterogeneity 6 , 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.