The transcriptional landscape of Shh medulloblastoma
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The transcriptional landscape of Shh medulloblastoma. / 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.
in: NAT COMMUN, Jahrgang 12, Nr. 1, 19.03.2021, S. 1749.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - The transcriptional landscape of Shh medulloblastoma
AU - Skowron, Patryk
AU - Farooq, Hamza
AU - Cavalli, Florence M G
AU - Morrissy, A Sorana
AU - Ly, Michelle
AU - Hendrikse, Liam D
AU - Wang, Evan Y
AU - Djambazian, Haig
AU - Zhu, Helen
AU - Mungall, Karen L
AU - Trinh, Quang M
AU - Zheng, Tina
AU - Dai, Shizhong
AU - Stucklin, Ana S Guerreiro
AU - Vladoiu, Maria C
AU - Fong, Vernon
AU - Holgado, Borja L
AU - Nor, Carolina
AU - Wu, Xiaochong
AU - Abd-Rabbo, Diala
AU - Bérubé, Pierre
AU - Wang, Yu Chang
AU - Luu, Betty
AU - Suarez, Raul A
AU - Rastan, Avesta
AU - Gillmor, Aaron H
AU - Lee, John J Y
AU - Zhang, Xiao Yun
AU - Daniels, Craig
AU - Dirks, Peter
AU - Malkin, David
AU - Bouffet, Eric
AU - Tabori, Uri
AU - Loukides, James
AU - Doz, François P
AU - Bourdeaut, Franck
AU - Delattre, Olivier O
AU - Masliah-Planchon, Julien
AU - Ayrault, Olivier
AU - Kim, Seung-Ki
AU - Meyronet, David
AU - Grajkowska, Wieslawa A
AU - Carlotti, Carlos G
AU - de Torres, Carmen
AU - Mora, Jaume
AU - Eberhart, Charles G
AU - Van Meir, Erwin G
AU - Kumabe, Toshihiro
AU - French, Pim J
AU - Kros, Johan M
AU - Jabado, Nada
AU - Lach, Boleslaw
AU - Pollack, Ian F
AU - Hamilton, Ronald L
AU - Rao, Amulya A Nageswara
AU - Giannini, Caterina
AU - Olson, James M
AU - Bognár, László
AU - Klekner, Almos
AU - Zitterbart, Karel
AU - Phillips, Joanna J
AU - Thompson, Reid C
AU - Cooper, Michael K
AU - Rubin, Joshua B
AU - Liau, Linda M
AU - Garami, Miklós
AU - Hauser, Peter
AU - Li, Kay Ka Wai
AU - Ng, Ho-Keung
AU - Poon, Wai Sang
AU - Yancey Gillespie, G
AU - Chan, Jennifer A
AU - Jung, Shin
AU - McLendon, Roger E
AU - Thompson, Eric M
AU - Zagzag, David
AU - Vibhakar, Rajeev
AU - Ra, Young Shin
AU - Garre, Maria Luisa
AU - Schüller, Ulrich
AU - Shofuda, Tomoko
AU - Faria, Claudia C
AU - López-Aguilar, Enrique
AU - Zadeh, Gelareh
AU - Hui, Chi-Chung
AU - Ramaswamy, Vijay
AU - Bailey, Swneke D
AU - Jones, Steven J
AU - Mungall, Andrew J
AU - Moore, Richard A
AU - Calarco, John A
AU - Stein, Lincoln D
AU - Bader, Gary D
AU - Reimand, Jüri
AU - Ragoussis, Jiannis
AU - Weiss, William A
AU - Marra, Marco A
AU - Suzuki, Hiromichi
AU - Taylor, Michael D
PY - 2021/3/19
Y1 - 2021/3/19
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Cerebellar Neoplasms/genetics
KW - Child
KW - Child, Preschool
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Gene Regulatory Networks
KW - Genetic Variation
KW - Hedgehog Proteins/genetics
KW - Humans
KW - Infant
KW - Male
KW - Medulloblastoma/genetics
KW - Middle Aged
KW - Signal Transduction/genetics
KW - Transcriptome
KW - Young Adult
U2 - 10.1038/s41467-021-21883-0
DO - 10.1038/s41467-021-21883-0
M3 - SCORING: Journal article
C2 - 33741928
VL - 12
SP - 1749
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -