A study by a Quebec-based team that includes several TFRI-funded researchers has uncovered a key mutation that leads to the development of an aggressive form of pediatric brain cancer known as high-grade glioma.
In a paper published in Cell (December 2020), the team found that many patients with a subtype of gliomas known as G34R/V high-grade gliomas (G34R/V HGGs) showed a high frequency of activating mutations in a gene called PDGFRA. According to the team, this gene activates a downstream mechanism known as the MAPK pathway, which drives cell division and growth.
This finding is significant because it suggests that this subtype of gliomas acts differently than others and could provide a new therapeutic target for a cancer that currently has no known treatments.
“These mechanisms have important therapeutic implications because G34R/V HGGs are invariably lethal, and PDGFRA mutations and downstream MAPK activation are potentially actionable targets, providing hope for novel therapeutic opportunities in this deadly cancer,” said Dr. Carol Chen, a postdoctoral fellow at McGill University and one of the paper’s first co-authors.
A video of first authors discussing their finding can be found here: https://jrnlclub.org/research-films/h33g34-pdgfra-gliomagenesis
Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis
Carol C.L. Chen, Shriya Deshmukh, Selin Jessa, Djihad Hadjadj, Veronique Lisi, Augusto Faria Andrade, Damien Faury, Wajih Jawhar, Rola Dali, Hiromichi Suzuki, Manav Pathania, Deli A, Frank Dubois, Eleanor Woodward, Steven Hébert, Marie Coutelier, Jason Karamchandani, Steffen Albrecht, Sebastian Brandner, Nicolas De Jay, Tenzin Gayden, Andrea Bajic, Ashot S. Harutyunyan, Dylan M. Marchione, Leonie G. Mikael, Nikoleta Juretic, Michele Zeinieh, Caterina Russo, Nicola Maestro, Angelia V. Bassenden, Peter Hauser, József Virga, Laszlo Bognar, Almos Klekner, Michal Zapotocky, Ales Vicha, Lenka Krskova, Katerina Vanova, Josef Zamecnik, David Sumerauer, Paul G. Ekert, David S. Ziegler, Benjamin Ellezam, Mariella G. Filbin, Mathieu Blanchette, Jordan R. Hansford, Dong-Anh Khuong-Quang, Albert M. Berghuis, Alexander G. Weil, Benjamin A. Garcia, Livia Garzia, Stephen C. Mack, Rameen Beroukhim, Keith L. Ligon, Michael D. Taylor, Pratiti Bandopadhayay, Christoph Kramm, Stefan M. Pfister, Andrey Korshunov, Dominik Sturm, David T.W. Jones, Paolo Salomoni, Claudia L. Kleinman, and Nada Jabado
This work was supported in part by funding from TFRI to Michael D. Taylor through a Terry Fox Translational Research Program Grant to Stratifying and targeting pediatric medulloblastoma through genomics