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Clonal evolution of glioblastoma under therapy

Cited 495 time in Web of Science Cited 516 time in Scopus

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

Issue Date
Nature Publishing Group
Nature Genetics, Vol.48 No.7, pp.768-776
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-b pathway as a potential therapeutic target in GBM.
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  • College of Medicine
  • Department of Medicine
Research Area 3D drug screening, Cancer Organoid, Precision Oncologuy


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