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 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

doi:10.1038/s41467-021-21883-0

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 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-RabboPierre 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

54 Citations (Scopus)

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.

Original language	English
Article number	1749
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21883-0
Publication status	Published - 19 Mar 2021

Bibliographical note

Funding Information:
M.D.T. is supported by the NIH (R01CA148699 and R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan’s Walk, SWIFTY Foundation, The Brain Tumour Charity, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research, and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant, a Cancer Research UK‘ Brain Tumour Award, and by a Stand Up To Cancer (SU2C) St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19-15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is also supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. F.M.G.C. is supported by the Stephen Buttrum Brain Tumor Research Fellowship, granted by the Brain Tumor Foundation of Canada. A.S. M. is supported by the Cancer Research Society Scholarships for the Next Generation of Scientists. P.S is supported by Sickkids Restracomp Ph.D. scholarship, and by funding provided by the Government of Ontario. The authors would like to thank Jim Loukides (Manager, Brain Tumour Biobank at SickKids) and recognize the Labatt Brain Tumour Research Centre and The Michael and Amira Dan Brain Tumour Bank Network. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), GTEx Project March 5, 2014 version Page 5 of 8 Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). This work was supported by NRNB (U.S. National Institutes of Health, National Center for Research Resources grant number P41 GM103504). A.K. was supported by the 2017-1.2.1-NKP-2017-00002 National Brain Research Program NAP 2.0 of Hungary. Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics and on the Niagara supercomputer at the SciNet HPC Consortium. SciNet is funded by the Canada Foundation for Innovation under the auspices of Compute Canada; the Government of Ontario; the Ontario Research Fund-Research Excellence; and the University of Toronto.

Publisher Copyright:
© 2021, The Author(s).

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10.1038/s41467-021-21883-0

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Skowron, P., Farooq, H., Cavalli, F. M. G., Morrissy, A. S., Ly, M., Hendrikse, L. D., Wang, E. Y., Djambazian, H., Zhu, H., Mungall, K. L., Trinh, Q. M., Zheng, T., Dai, S., Stucklin, A. S. G., Vladoiu, M. C., Fong, V., Holgado, B. L., Nor, C., Wu, X., ... Taylor, M. D. (2021). The transcriptional landscape of Shh medulloblastoma. Nature Communications, 12(1), Article 1749. https://doi.org/10.1038/s41467-021-21883-0

@article{b2ed7bf87ab548468b3856ffee459d4c,

title = "The transcriptional landscape of Shh medulloblastoma",

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.",

author = "Patryk Skowron and Hamza Farooq and Cavalli, {Florence M.G.} and Morrissy, {A. Sorana} and Michelle Ly and Hendrikse, {Liam D.} and Wang, {Evan Y.} and Haig Djambazian and Helen Zhu and Mungall, {Karen L.} and Trinh, {Quang M.} and Tina Zheng and Shizhong Dai and Stucklin, {Ana S.Guerreiro} and Vladoiu, {Maria C.} and Vernon Fong and Holgado, {Borja L.} and Carolina Nor and Xiaochong Wu and Diala Abd-Rabbo and Pierre B{\'e}rub{\'e} and Wang, {Yu Chang} and Betty Luu and Suarez, {Raul A.} and Avesta Rastan and Gillmor, {Aaron H.} and Lee, {John J.Y.} and Zhang, {Xiao Yun} and Craig Daniels and Peter Dirks and David Malkin and Eric Bouffet and Uri Tabori and James Loukides and Doz, {Fran{\c c}ois P.} and Franck Bourdeaut and Delattre, {Olivier O.} and Julien Masliah-Planchon and Olivier Ayrault and Kim, {Seung Ki} and David Meyronet and Grajkowska, {Wieslawa A.} and Carlotti, {Carlos G.} and {de Torres}, Carmen and Jaume Mora and Eberhart, {Charles G.} and {Van Meir}, {Erwin G.} and Toshihiro Kumabe and French, {Pim J.} and Kros, {Johan M.} and Nada Jabado and Boleslaw Lach and Pollack, {Ian F.} and Hamilton, {Ronald L.} and Rao, {Amulya A.Nageswara} and Caterina Giannini and Olson, {James M.} and L{\'a}szl{\'o} Bogn{\'a}r and Almos Klekner and Karel Zitterbart and Phillips, {Joanna J.} and Thompson, {Reid C.} and Cooper, {Michael K.} and Rubin, {Joshua B.} and Liau, {Linda M.} and Mikl{\'o}s Garami and Peter Hauser and Li, {Kay Ka Wai} and Ng, {Ho Keung} and Poon, {Wai Sang} and {Yancey Gillespie}, G. and Chan, {Jennifer A.} and Shin Jung and McLendon, {Roger E.} and Thompson, {Eric M.} and David Zagzag and Rajeev Vibhakar and Ra, {Young Shin} and Garre, {Maria Luisa} and Ulrich Sch{\"u}ller and Tomoko Shofuda and Faria, {Claudia C.} and Enrique L{\'o}pez-Aguilar and Gelareh Zadeh and Hui, {Chi Chung} and Vijay Ramaswamy and Bailey, {Swneke D.} and Jones, {Steven J.} and Mungall, {Andrew J.} and Moore, {Richard A.} and Calarco, {John A.} and Stein, {Lincoln D.} and Bader, {Gary D.} and J{\"u}ri Reimand and Jiannis Ragoussis and Weiss, {William A.} and Marra, {Marco A.} and Hiromichi Suzuki and Taylor, {Michael D.}",

note = "Funding Information: M.D.T. is supported by the NIH (R01CA148699 and R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan{\textquoteright}s Walk, SWIFTY Foundation, The Brain Tumour Charity, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research, and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant, a Cancer Research UK{\textquoteleft} Brain Tumour Award, and by a Stand Up To Cancer (SU2C) St. Baldrick{\textquoteright}s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19-15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is also supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. F.M.G.C. is supported by the Stephen Buttrum Brain Tumor Research Fellowship, granted by the Brain Tumor Foundation of Canada. A.S. M. is supported by the Cancer Research Society Scholarships for the Next Generation of Scientists. P.S is supported by Sickkids Restracomp Ph.D. scholarship, and by funding provided by the Government of Ontario. The authors would like to thank Jim Loukides (Manager, Brain Tumour Biobank at SickKids) and recognize the Labatt Brain Tumour Research Centre and The Michael and Amira Dan Brain Tumour Bank Network. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), GTEx Project March 5, 2014 version Page 5 of 8 Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). This work was supported by NRNB (U.S. National Institutes of Health, National Center for Research Resources grant number P41 GM103504). A.K. was supported by the 2017-1.2.1-NKP-2017-00002 National Brain Research Program NAP 2.0 of Hungary. Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics and on the Niagara supercomputer at the SciNet HPC Consortium. SciNet is funded by the Canada Foundation for Innovation under the auspices of Compute Canada; the Government of Ontario; the Ontario Research Fund-Research Excellence; and the University of Toronto. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = mar,

day = "19",

doi = "10.1038/s41467-021-21883-0",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Skowron, P, Farooq, H, Cavalli, FMG, Morrissy, AS, Ly, M, Hendrikse, LD, Wang, EY, Djambazian, H, Zhu, H, Mungall, KL, Trinh, QM, Zheng, T, Dai, S, Stucklin, ASG, Vladoiu, MC, Fong, V, Holgado, BL, Nor, C, Wu, X, Abd-Rabbo, D, Bérubé, P, Wang, YC, Luu, B, Suarez, RA, Rastan, A, Gillmor, AH, Lee, JJY, Zhang, XY, Daniels, C, Dirks, P, Malkin, D, Bouffet, E, Tabori, U, Loukides, J, Doz, FP, Bourdeaut, F, Delattre, OO, Masliah-Planchon, J, Ayrault, O, Kim, SK, Meyronet, D, Grajkowska, WA, Carlotti, CG, de Torres, C, Mora, J, Eberhart, CG, Van Meir, EG, Kumabe, T, French, PJ, Kros, JM, Jabado, N, Lach, B, Pollack, IF, Hamilton, RL, Rao, AAN, Giannini, C, Olson, JM, Bognár, L, Klekner, A, Zitterbart, K, Phillips, JJ, Thompson, RC, Cooper, MK, Rubin, JB, Liau, LM, Garami, M, Hauser, P, Li, KKW, Ng, HK, Poon, WS, Yancey Gillespie, G, Chan, JA, Jung, S, McLendon, RE, Thompson, EM, Zagzag, D, Vibhakar, R, Ra, YS, Garre, ML, Schüller, U, Shofuda, T, Faria, CC, López-Aguilar, E, Zadeh, G, Hui, CC, Ramaswamy, V, Bailey, SD, Jones, SJ, Mungall, AJ, Moore, RA, Calarco, JA, Stein, LD, Bader, GD, Reimand, J, Ragoussis, J, Weiss, WA, Marra, MA, Suzuki, H & Taylor, MD 2021, 'The transcriptional landscape of Shh medulloblastoma', Nature Communications, vol. 12, no. 1, 1749. https://doi.org/10.1038/s41467-021-21883-0

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.

N1 - Funding Information: M.D.T. is supported by the NIH (R01CA148699 and R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan’s Walk, SWIFTY Foundation, The Brain Tumour Charity, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research, and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant, a Cancer Research UK‘ Brain Tumour Award, and by a Stand Up To Cancer (SU2C) St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19-15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is also supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. F.M.G.C. is supported by the Stephen Buttrum Brain Tumor Research Fellowship, granted by the Brain Tumor Foundation of Canada. A.S. M. is supported by the Cancer Research Society Scholarships for the Next Generation of Scientists. P.S is supported by Sickkids Restracomp Ph.D. scholarship, and by funding provided by the Government of Ontario. The authors would like to thank Jim Loukides (Manager, Brain Tumour Biobank at SickKids) and recognize the Labatt Brain Tumour Research Centre and The Michael and Amira Dan Brain Tumour Bank Network. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), GTEx Project March 5, 2014 version Page 5 of 8 Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). This work was supported by NRNB (U.S. National Institutes of Health, National Center for Research Resources grant number P41 GM103504). A.K. was supported by the 2017-1.2.1-NKP-2017-00002 National Brain Research Program NAP 2.0 of Hungary. Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics and on the Niagara supercomputer at the SciNet HPC Consortium. SciNet is funded by the Canada Foundation for Innovation under the auspices of Compute Canada; the Government of Ontario; the Ontario Research Fund-Research Excellence; and the University of Toronto. Publisher Copyright: © 2021, The Author(s).

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.

UR - http://www.scopus.com/inward/record.url?scp=85102687135&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-21883-0

DO - 10.1038/s41467-021-21883-0

M3 - Article

C2 - 33741928

AN - SCOPUS:85102687135

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1749

ER -

The transcriptional landscape of Shh medulloblastoma

Abstract

Bibliographical note

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