The transcriptional landscape of Shh medulloblastoma

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demo...

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Detalles Bibliográficos
Autores principales: Skowron, Patryk, Farooq, Hamza, Cavalli, Florence M. G., Morrissy, A. Sorana, Ly, Michelle, Hendrikse, Liam D., Wang, Evan Y., Djambazian, Haig, Zhu, Helen, Mungall, Karen L., Trinh, Quang M., Zheng, Tina, Dai, Shizhong, Stucklin, Ana S. Guerreiro, Vladoiu, Maria C., Fong, Vernon, Holgado, Borja L., Nor, Carolina, Wu, Xiaochong, Abd-Rabbo, Diala, Bérubé, Pierre, Wang, Yu Chang, Luu, Betty, Suarez, Raul A., Rastan, Avesta, Gillmor, Aaron H., Lee, John J. Y., Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, James, Doz, François P., Bourdeaut, Franck, Delattre, Olivier O., Masliah-Planchon, Julien, Ayrault, Olivier, Kim, Seung-Ki, Meyronet, David, Grajkowska, Wieslawa A., Carlotti, Carlos G., de Torres, Carmen, Mora, Jaume, Eberhart, Charles G., Van Meir, Erwin G., Kumabe, Toshihiro, French, Pim J., Kros, Johan M., Jabado, Nada, Lach, Boleslaw, Pollack, Ian F., Hamilton, Ronald L., Rao, Amulya A. Nageswara, Giannini, Caterina, Olson, James M., Bognár, László, Klekner, Almos, Zitterbart, Karel, Phillips, Joanna J., Thompson, Reid C., Cooper, Michael K., Rubin, Joshua B., Liau, Linda M., Garami, Miklós, Hauser, Peter, Li, Kay Ka Wai, Ng, Ho-Keung, Poon, Wai Sang, Yancey Gillespie, G., Chan, Jennifer A., Jung, Shin, McLendon, Roger E., Thompson, Eric M., Zagzag, David, Vibhakar, Rajeev, Ra, Young Shin, Garre, Maria Luisa, Schüller, Ulrich, Shofuda, Tomoko, Faria, Claudia C., López-Aguilar, Enrique, Zadeh, Gelareh, Hui, Chi-Chung, Ramaswamy, Vijay, Bailey, Swneke D., Jones, Steven J., Mungall, Andrew J., Moore, Richard A., Calarco, John A., Stein, Lincoln D., Bader, Gary D., Reimand, Jüri, Ragoussis, Jiannis, Weiss, William A., Marra, Marco A., Suzuki, Hiromichi, Taylor, Michael D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979819/
https://www.ncbi.nlm.nih.gov/pubmed/33741928
http://dx.doi.org/10.1038/s41467-021-21883-0
Descripción
Sumario:Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

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