The transcriptional landscape of Shh medulloblastoma
Patryk Skowron, Hamza Farooq, Florence M.G. Cavalli, A. Sorana Morrissy, Michelle Ly, Liam D. Hendrikse, Evan Y. Wang, Haig Djambazian, Helen Zhu, Karen Mungall, Quang M. Trinh, Tina Zheng, Shizhong Dai, Ana Guerreiro Stücklin, Maria Vladoiu, Vernon Fong, Borja Holgado, Carolina Nör, Xiaochong Wu, Diala Abd-Rabbo, Pierre Bérubé, Yu Chang Wang, Betty Luu, Raúl A. Suárez, Avesta Rastan, Aaron H. Gillmor, John J. Y. Lee, Xiaoyun Zhang, Craig Daniels, Peter B. Dirks, David Malkin, Éric Bouffet, Uri Tabori, James Loukides, François Doz, Franck Bourdeaut, Olivier Delattre, Julien Masliah‐Planchon, Olivier Ayrault, Seung‐Ki Kim, David Meyronet, Wiesława Grajkowska, Carlos Gilberto Carlotti, Carmen de Torres, Jaume Mora, Charles G. Eberhart, Erwin G. Van Meir, Toshihiro Kumabe, Pim J. French, Johan M. Kros, Nada Jabado, Bolesław Lach, Ian F. Pollack, Ronald L. Hamilton, Amulya A. Nageswara Rao, Caterina Giannini, James M. Olson, László Bognár, Álmos Klekner, Karel Zitterbart, Joanna J. Phillips, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Linda M. Liau, Miklós Garami, Péter 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 Seob Shin, Maria Luisa Garrè, Ulrich Schüller, Tomoko Shofuda, Cláudia C. Faria, Enrique López‐Aguilar, Gelareh Zadeh, Chi‐chung Hui, Vijay Ramaswamy, Swneke D. Bailey, Steven J.M. Jones, Andrew J. Mungall, Richard A. Moore, John A. Calarco, Lincoln Stein, Gary D. Bader, Jüri Reimand, Jiannis Ragoussis, William A. Weiss, Marco A. Marra, Hiromichi Suzuki, Michael D. Taylor, Michael D. Taylor
Abstract
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.