A new international study led by researchers partly funded by the TFRI has uncovered a number of genes that drive cancer in a subset of patients with medulloblastoma, the most common brain tumour affecting children.
The study, published in Nature Communications (March 2021), used unbiased sequencing of the transcriptome across a large cohort of 250 tumours from patients with Sonic hedgehog medulloblastoma, a molecularly and clinically distinct subtype of the disease. This analysis revealed a number of unknown molecular differences within this medulloblastoma subtype, and demonstrated the previously unappreciated importance of non-coding RNA transcripts.
“Being able to put together such a large transcriptional dataset is a challenge in and of itself,” said Dr. Patryk Skowron, a bioinformatician at the Hospital for Sick Kids and the study’s first author. “Fortunately, the payoff has been enormous, and it has given us the opportunity to study this cancer in remarkable detail which allowed us to reveal many missed genes and therapeutic pathways.”
We reached out to Dr. Skowron to learn more about the findings.
TFRI: What would you highlight as the most important finding of this paper?
PS: It’s hard to pinpoint one finding which stands out more than the rest. I would say the most important discovery is really the sum of all the novel cancer driver genes which we identified and how they fall into known biological pathways. A good example would be MYCN, part of the cell cycle pathway; it has been a known oncogene in medulloblastoma for decades. Now we have identified inactivating mutations in its negative regulator FBXW7 which indirectly activate MYCN in 20 per cent of patients.
How is this finding helping to advance the science of cancer?
The discovery and characterization of these novel drivers opens up many opportunities for molecular studies. We are already using these results to make new disease models and numerous groups—national and international—are asking us for the data so that they can gain more insight into their own research. We are excited to see what new angles of therapy can be discovered using this data.
What foreseeable impact could this discovery have on cancer patients?
In the era of personalized medicine, it is important to understand which genes are drivers and which are bystanders. The clearer the picture we can get of the mutational landscape of medulloblastoma, the better equipped we are to discover and test molecular therapies. There is still a lot of work to be done, but I do see a future where high-risk medulloblastoma patients are successfully treated with specific molecular therapies alongside the standard of care. Ultimately all of our research is about helping patients.
Is there anything else you think is important to highlight about this paper?
That international collaboration is essential in cancer research, and this is something our lab believes strongly. A short look at the author list shows what a massive study this was, involving the global pediatric cancer community. We had help from numerous groups and have been receiving samples from institutions around the world. Without their help we would not have the power to study medulloblastoma in such detail and make such an impact—for this, we would like to thank them.
Study
The transcriptional landscape of Shh medulloblastoma
Authors
Patryk Skowron, Hamza Farooq, Florence M. G. Cavalli, A. Sorana Morrissy, Michelle Ly, Liam D. Hendrikse, Evan Y. Wang, Haig Djambazian, Helen Zhu, Karen L. Mungall, Quang M. Trinh, Tina Zheng, Shizhong Dai, Ana S. Guerreiro Stucklin, Maria C. Vladoiu, Vernon Fong, Borja L. Holgado, Carolina Nor, Xiaochong Wu, Diala Abd-Rabbo, Pierre Bérubé, Yu Chang Wang, Betty Luu, Raul A. Suarez, Avesta Rastan, Aaron H. Gillmor, John J. Y. Lee, Xiao Yun Zhang, Craig Daniels, Peter Dirks, David Malkin, Eric Bouffet, Uri Tabori, James Loukides, François P. Doz, Franck Bourdeaut, Olivier O. Delattre, Julien Masliah-Planchon, Olivier Ayrault, Seung-Ki Kim, David Meyronet, Wieslawa A. Grajkowska, Carlos G. Carlotti, Carmen de Torres, Jaume Mora, Charles G. Eberhart, Erwin G. Van Meir, Toshihiro Kumabe, Pim J. French, Johan M. Kros, Nada Jabado, Boleslaw Lach, Ian F. Pollack, Ronald L. Hamilton, Amulya A. Nageswara Rao, Caterina Giannini, James M. Olson, László Bognár, Almos Klekner, Karel Zitterbart, Joanna J. Phillips, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Linda M. Liau, Miklós Garami, Peter Hauser, Kay Ka Wai Li, Ho-Keung Ng, Wai Sang Poon, G. Yancey Gillespie, Jennifer A. Chan, Shin Jung, Roger E. McLendon, Eric M. Thompson, David Zagzag, Rajeev Vibhakar, Young Shin Ra, Maria Luisa Garre, Ulrich Schüller, Tomoko Shofuda, Claudia C. Faria, Enrique López-Aguilar, Gelareh Zadeh, Chi-Chung Hui, Vijay Ramaswamy, Swneke D. Bailey, Steven J. Jones, Andrew J. Mungall, Richard A. Moore, John A. Calarco, Lincoln D. Stein, Gary D. Bader, Jüri Reimand, Jiannis Ragoussis, William A. Weiss, Marco A. Marra, Hiromichi Suzuki & Michael D. Taylor
Funding
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