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-beta. Silencing LTBP4 in GBM cells leads to suppression of TGF-beta activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-beta pathway as a potential therapeutic target in GBM.
Description
Clonal evolution of glioblastoma under therapy : Nature Genetics : Nature Research
%0 Journal Article
%1 wang2016clonal
%A Wang, Jiguang
%A Cazzato, Emanuela
%A Ladewig, Erik
%A Frattini, Veronique
%A Rosenbloom, Daniel I S
%A Zairis, Sakellarios
%A Abate, Francesco
%A Liu, Zhaoqi
%A Elliott, Oliver
%A Shin, Yong-Jae
%A Lee, Jin-Ku
%A Lee, In-Hee
%A Park, Woong-Yang
%A Eoli, Marica
%A Blumberg, Andrew J
%A Lasorella, Anna
%A Nam, Do-Hyun
%A Finocchiaro, Gaetano
%A Iavarone, Antonio
%A Rabadan, Raul
%D 2016
%I Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
%J Nat Genet
%K evolution glioblastoma tcga
%N 7
%P 768--776
%T Clonal evolution of glioblastoma under therapy
%U http://dx.doi.org/10.1038/ng.3590
%V 48
%X 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-beta. Silencing LTBP4 in GBM cells leads to suppression of TGF-beta activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-beta pathway as a potential therapeutic target in GBM.
@article{wang2016clonal,
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-[beta]. Silencing LTBP4 in GBM cells leads to suppression of TGF-[beta] activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-[beta] pathway as a potential therapeutic target in GBM.},
added-at = {2017-05-17T18:54:55.000+0200},
author = {Wang, Jiguang and Cazzato, Emanuela and Ladewig, Erik and Frattini, Veronique and Rosenbloom, Daniel I S and Zairis, Sakellarios and Abate, Francesco and Liu, Zhaoqi and Elliott, Oliver and Shin, Yong-Jae and Lee, Jin-Ku and Lee, In-Hee and Park, Woong-Yang and Eoli, Marica and Blumberg, Andrew J and Lasorella, Anna and Nam, Do-Hyun and Finocchiaro, Gaetano and Iavarone, Antonio and Rabadan, Raul},
biburl = {https://www.bibsonomy.org/bibtex/22bb22fdbc30d0905367755525938f7ae/marcsaric},
description = {Clonal evolution of glioblastoma under therapy : Nature Genetics : Nature Research},
interhash = {f4e72d29672c250157dfb122e085ae65},
intrahash = {2bb22fdbc30d0905367755525938f7ae},
issn = {10614036},
journal = {Nat Genet},
keywords = {evolution glioblastoma tcga},
month = jul,
number = 7,
pages = {768--776},
publisher = {Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.},
timestamp = {2017-05-17T18:54:55.000+0200},
title = {Clonal evolution of glioblastoma under therapy},
url = {http://dx.doi.org/10.1038/ng.3590},
volume = 48,
year = 2016
}