Clonal evolution of glioblastoma under therapy

Jiguang Wang, Emanuela Cazzato, Erik Ladewig, Veronique Frattini, Daniel I S Rosenbloom, Sakellarios Zairis, Francesco Abate, Zhaoqi Liu, Oliver Elliott, Yong Jae Shin, Jin Ku Lee, In Hee Lee, Woong Yang Park, Marica Eoli, Andrew J. Blumberg, Anna Lasorella, Do Hyun Nam, Gaetano Finocchiaro, Antonio Iavarone, Raul Rabadan

Research output: Contribution to journalArticle

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. To better understand how GBM evolves, we analyzed longitudinal genomic and transcriptomic data from 114 patients. The analysis shows a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern, together with estimates of evolutionary rate, suggests that relapse-associated clones typically existed years before diagnosis. Fifteen percent of tumors present hypermutation at relapse in highly expressed genes, with a clear mutational signature. We find that 11% of recurrence tumors harbor mutations in LTBP4, which encodes a protein binding to TGF-β. Silencing LTBP4 in GBM cells leads to suppression of TGF-β activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-β pathway as a potential therapeutic target in GBM.

Original languageEnglish
Pages (from-to)768-776
Number of pages9
JournalNature Genetics
Volume48
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

    Fingerprint

ASJC Scopus subject areas

  • Genetics

Cite this

Wang, J., Cazzato, E., Ladewig, E., Frattini, V., Rosenbloom, D. I. S., Zairis, S., Abate, F., Liu, Z., Elliott, O., Shin, Y. J., Lee, J. K., Lee, I. H., Park, W. Y., Eoli, M., Blumberg, A. J., Lasorella, A., Nam, D. H., Finocchiaro, G., Iavarone, A., & Rabadan, R. (2016). Clonal evolution of glioblastoma under therapy. Nature Genetics, 48(7), 768-776. https://doi.org/10.1038/ng.3590