Clonal evolution of glioblastoma under therapy.
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.
Department of Systems Biology, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.
Jiguang
J
Wang
Fondazione IRCCS Istituto Neurologico Besta, Unit of Molecular Neuro-Oncology, Milan, Italy.
Emanuela
E
Cazzato
Department of Systems Biology, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.
Erik
E
Ladewig
Institute for Cancer Genetics, Columbia University, New York, New York, USA.
Veronique
V
Frattini
Department of Systems Biology, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.
Daniel I S
0000-0003-1413-3907
DI
Rosenbloom
Department of Systems Biology, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.
Sakellarios
S
Zairis
Department of Systems Biology, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.
Francesco
F
Abate
Department of Systems Biology, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.
Zhaoqi
Z
Liu
Department of Systems Biology, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.
Oliver
O
Elliott
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Yong-Jae
YJ
Shin
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Jin-Ku
JK
Lee
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
In-Hee
IH
Lee
Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Woong-Yang
WY
Park
Fondazione IRCCS Istituto Neurologico Besta, Unit of Molecular Neuro-Oncology, Milan, Italy.
Marica
M
Eoli
Department of Mathematics, University of Texas, Austin, Texas, USA.
Andrew J
AJ
Blumberg
Institute for Cancer Genetics, Columbia University, New York, New York, USA.|Department of Pediatrics, Columbia University, New York, New York, USA.|Department of Pathology, Columbia University, New York, New York, USA.
Anna
A
Lasorella
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
Do-Hyun
DH
Nam
Fondazione IRCCS Istituto Neurologico Besta, Unit of Molecular Neuro-Oncology, Milan, Italy.
Gaetano
G
Finocchiaro
Institute for Cancer Genetics, Columbia University, New York, New York, USA.|Department of Pathology, Columbia University, New York, New York, USA.|Department of Neurology, Columbia University, New York, New York, USA.
Antonio
A
Iavarone
Department of Systems Biology, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Columbia University, New York, New York, USA.
Raul
R
Rabadan
D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D060965:Clonal Evolution / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics; D008137:Longitudinal Studies; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015996:Survival Rate; D000077204:Temozolomide; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide