Divergent clonal selection dominates medulloblastoma at recurrence

A. Sorana Morrissy; Livia Garzia; David J H Shih; Scott Zuyderduyn; Xi Huang; Patryk Skowron; Marc Remke; Florence M G Cavalli; Vijay Ramaswamy; Patricia E. Lindsay; Salomeh Jelveh; Laura K. Donovan; Xin Wang; Betty Luu; Kory Zayne; Yisu Li; Chelsea Mayoh; Nina Thiessen; Eloi Mercier; Karen L. Mungall; Yusanne Ma; Kane Tse; Thomas Zeng; Karey Shumansky; Andrew J L Roth; Sohrab Shah; Hamza Farooq; Noriyuki Kijima; Borja L. Holgado; John J Y Lee; Stuart Matan-Lithwick; Jessica Liu; Stephen C. Mack; Alex Manno; K. A. Michealraj; Carolina Nor; John Peacock; Lei Qin; Juri Reimand; Adi Rolider; Yuan Y. Thompson; Xiaochong Wu; Trevor Pugh; Adrian Ally; Mikhail Bilenky; Yaron S N Butterfield; Rebecca Carlsen; Young Cheng; Eric Chuah; Richard D. Corbett; Noreen Dhalla; An He; Darlene Lee; Haiyan I. Li; William Long; Michael Mayo; Patrick Plettner; Jenny Q. Qian; Jacqueline E. Schein; Angela Tam; Tina Wong; Inanc Birol; Yongjun Zhao; Claudia C. Faria; José Pimentel; Sofia Nunes; Tarek Shalaby; Michael Grotzer; Ian F. Pollack; Ronald L. Hamilton; Xiao Nan Li; Anne E. Bendel; Daniel W. Fults; Andrew W. Walter; Toshihiro Kumabe; Teiji Tominaga; V. Peter Collins; Yoon Jae Cho; Caitlin Hoffman; David Lyden; Jeffrey H. Wisoff; James H. Garvin; Duncan S. Stearns; Luca Massimi; Ulrich Schüller; Jaroslav Sterba; Karel Zitterbart; Stephanie Puget; Olivier Ayrault; Sandra E. Dunn; Daniela P C Tirapelli; Carlos G. Carlotti; Helen Wheeler; Andrew R. Hallahan; Wendy Ingram; Tobey J. MacDonald; Jeffrey J. Olson; Erwin G. Van Meir; Ji Yeoun Lee; Kyu Chang Wang; Seung Ki Kim; Byung Kyu Cho; Torsten Pietsch; Gudrun Fleischhack; Stephan Tippelt; Young Shin Ra; Simon Bailey; Janet C. Lindsey; Steven C. Clifford; Charles G. Eberhart; Michael K. Cooper; Roger J. Packer; Maura Massimino; Maria Luisa Garre; Ute Bartels; Uri Tabori; Cynthia E. Hawkins; Peter Dirks; Eric Bouffet; James T. Rutka; Robert J. Wechsler-Reya; William A. Weiss; Lara S. Collier; Adam J. Dupuy; Andrey Korshunov; David T W Jones; Marcel Kool; Paul A. Northcott; Stefan M. Pfister; David A. Largaespada; Andrew J. Mungall; Richard A. Moore; Nada Jabado; Gary D. Bader; Steven J M Jones; David Malkin; Marco A. Marra; Michael D. Taylor

doi:10.1038/nature16478

Divergent clonal selection dominates medulloblastoma at recurrence

A. Sorana Morrissy, Livia Garzia, David J H Shih, Scott Zuyderduyn, Xi Huang, Patryk Skowron, Marc Remke, Florence M G Cavalli, Vijay Ramaswamy, Patricia E. Lindsay, Salomeh Jelveh, Laura K. Donovan, Xin Wang, Betty Luu, Kory Zayne, Yisu Li, Chelsea Mayoh, Nina Thiessen, Eloi Mercier, Karen L. MungallYusanne Ma, Kane Tse, Thomas Zeng, Karey Shumansky, Andrew J L Roth, Sohrab Shah, Hamza Farooq, Noriyuki Kijima, Borja L. Holgado, John J Y Lee, Stuart Matan-Lithwick, Jessica Liu, Stephen C. Mack, Alex Manno, K. A. Michealraj, Carolina Nor, John Peacock, Lei Qin, Juri Reimand, Adi Rolider, Yuan Y. Thompson, Xiaochong Wu, Trevor Pugh, Adrian Ally, Mikhail Bilenky, Yaron S N Butterfield, Rebecca Carlsen, Young Cheng, Eric Chuah, Richard D. Corbett, Noreen Dhalla, An He, Darlene Lee, Haiyan I. Li, William Long, Michael Mayo, Patrick Plettner, Jenny Q. Qian, Jacqueline E. Schein, Angela Tam, Tina Wong, Inanc Birol, Yongjun Zhao, Claudia C. Faria, José Pimentel, Sofia Nunes, Tarek Shalaby, Michael Grotzer, Ian F. Pollack, Ronald L. Hamilton, Xiao Nan Li, Anne E. Bendel, Daniel W. Fults, Andrew W. Walter, Toshihiro Kumabe, Teiji Tominaga, V. Peter Collins, Yoon Jae Cho, Caitlin Hoffman, David Lyden, Jeffrey H. Wisoff, James H. Garvin, Duncan S. Stearns, Luca Massimi, Ulrich Schüller, Jaroslav Sterba, Karel Zitterbart, Stephanie Puget, Olivier Ayrault, Sandra E. Dunn, Daniela P C Tirapelli, Carlos G. Carlotti, Helen Wheeler, Andrew R. Hallahan, Wendy Ingram, Tobey J. MacDonald, Jeffrey J. Olson, Erwin G. Van Meir, Ji Yeoun Lee, Kyu Chang Wang, Seung Ki Kim, Byung Kyu Cho, Torsten Pietsch, Gudrun Fleischhack, Stephan Tippelt, Young Shin Ra, Simon Bailey, Janet C. Lindsey, Steven C. Clifford, Charles G. Eberhart, Michael K. Cooper, Roger J. Packer, Maura Massimino, Maria Luisa Garre, Ute Bartels, Uri Tabori, Cynthia E. Hawkins, Peter Dirks, Eric Bouffet, James T. Rutka, Robert J. Wechsler-Reya, William A. Weiss, Lara S. Collier, Adam J. Dupuy, Andrey Korshunov, David T W Jones, Marcel Kool, Paul A. Northcott, Stefan M. Pfister, David A. Largaespada, Andrew J. Mungall, Richard A. Moore, Nada Jabado, Gary D. Bader, Steven J M Jones, David Malkin, Marco A. Marra, Michael D. Taylor

Masonic Cancer Center

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

222 Scopus citations

Abstract

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

Original language	English (US)
Pages (from-to)	351-357
Number of pages	7
Journal	Nature
Volume	529
Issue number	7586
DOIs	https://doi.org/10.1038/nature16478
State	Published - Jan 21 2016

Bibliographical note

Funding Information:
Acknowledgements The MAGIC project is financially supported by: Genome Canada, Genome BC, Terry Fox Research Institute, Ontario Institute for Cancer Research, Pediatric Oncology Group Ontario, Funds from ‘The Family of Kathleen Lorette’ and the Clark H. Smith Brain Tumour Centre, Montreal Children’s Hospital Foundation, Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, B.R.A.I.N. Child, and BC Childhood Cancer Parents Association. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by The Canadian Cancer Society Research Institute, The Garron Family Chair in Childhood Cancer Research, and grants from the Cure Search for Children’s Cancer Foundation, the National Institutes of Health (R01CA148699 R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, Brainchild and The McLaughlin Centre at the University of Toronto. M.D.T. is also supported by the Swifty Foundation. L.G. was supported by the Davis M. Ferguson Memorial Fund at ABTA. Alex’s Lemonade Stand Young Investigator Award supported V.R. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. This work was also supported by a Program Project Grant from the Terry Fox Research Institute, and a Grand Challenge Award from CureSearch for Children’s Cancer. Additionally, this work was supported by the PedBrain Tumour Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). Funding by the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) to S.M.P., G.F. and T.P. The study was also financed by the Hungarian Brain Research Program Grant No. KTIA_13_NAP-A-V/3. and NAP-A-II/7. A.K. was supported by the János Bolyai scholarship of the Hungarian Academy of Sciences. E.G.V.M. was supported by NIH R01 grants CA163722 and NS096236, and St. Baldrick’s and Cure Childhood Cancer Foundations . We would like to acknowledge R. P. Hill (Ontario Cancer Institute), the Labatt Brain Tumour Research Centre Tumour and Tissue Repository, which is supported by B.R.A.I.N. Child and Megan’s Walk. M.R. is supported by a fellowship from the Dr. Mildred Scheel Foundation for Cancer Research/ German Cancer Aid. F.M.G.C. is supported by the Stephen Buttrum Brain Tumour Research Fellowship, granted by Brain Tumour Foundation of Canada. V.R. is supported by a CIHR fellowship and an Alberta Innovates-Health Solutions Clinical Fellowship. We would like to thank the Toronto Centre for Phenogenomics for animal housing and veterinary support, and the Preclinical Core II and animal research facility at STTARR (Spatiotemporal Targeting and Amplification of Radiation Response) in Toronto for assistance with CT-guided radiation experiments. We would like to thank Z. Wang for technical help with IHC, S. Archer for technical writing and C. Smith for artwork.

Publisher Copyright:
© 2016 Macmillan Publishers Limited. All rights reserved.

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http://europepmc.org/articles/pmc4936195

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Morrissy, A. S., Garzia, L., Shih, D. J. H., Zuyderduyn, S., Huang, X., Skowron, P., Remke, M., Cavalli, F. M. G., Ramaswamy, V., Lindsay, P. E., Jelveh, S., Donovan, L. K., Wang, X., Luu, B., Zayne, K., Li, Y., Mayoh, C., Thiessen, N., Mercier, E., ... Taylor, M. D. (2016). Divergent clonal selection dominates medulloblastoma at recurrence. Nature, 529(7586), 351-357. https://doi.org/10.1038/nature16478

Morrissy, AS, Garzia, L, Shih, DJH, Zuyderduyn, S, Huang, X, Skowron, P, Remke, M, Cavalli, FMG, Ramaswamy, V, Lindsay, PE, Jelveh, S, Donovan, LK, Wang, X, Luu, B, Zayne, K, Li, Y, Mayoh, C, Thiessen, N, Mercier, E, Mungall, KL, Ma, Y, Tse, K, Zeng, T, Shumansky, K, Roth, AJL, Shah, S, Farooq, H, Kijima, N, Holgado, BL, Lee, JJY, Matan-Lithwick, S, Liu, J, Mack, SC, Manno, A, Michealraj, KA, Nor, C, Peacock, J, Qin, L, Reimand, J, Rolider, A, Thompson, YY, Wu, X, Pugh, T, Ally, A, Bilenky, M, Butterfield, YSN, Carlsen, R, Cheng, Y, Chuah, E, Corbett, RD, Dhalla, N, He, A, Lee, D, Li, HI, Long, W, Mayo, M, Plettner, P, Qian, JQ, Schein, JE, Tam, A, Wong, T, Birol, I, Zhao, Y, Faria, CC, Pimentel, J, Nunes, S, Shalaby, T, Grotzer, M, Pollack, IF, Hamilton, RL, Li, XN, Bendel, AE, Fults, DW, Walter, AW, Kumabe, T, Tominaga, T, Collins, VP, Cho, YJ, Hoffman, C, Lyden, D, Wisoff, JH, Garvin, JH, Stearns, DS, Massimi, L, Schüller, U, Sterba, J, Zitterbart, K, Puget, S, Ayrault, O, Dunn, SE, Tirapelli, DPC, Carlotti, CG, Wheeler, H, Hallahan, AR, Ingram, W, MacDonald, TJ, Olson, JJ, Van Meir, EG, Lee, JY, Wang, KC, Kim, SK, Cho, BK, Pietsch, T, Fleischhack, G, Tippelt, S, Ra, YS, Bailey, S, Lindsey, JC, Clifford, SC, Eberhart, CG, Cooper, MK, Packer, RJ, Massimino, M, Garre, ML, Bartels, U, Tabori, U, Hawkins, CE, Dirks, P, Bouffet, E, Rutka, JT, Wechsler-Reya, RJ, Weiss, WA, Collier, LS, Dupuy, AJ, Korshunov, A, Jones, DTW, Kool, M, Northcott, PA, Pfister, SM, Largaespada, DA, Mungall, AJ, Moore, RA, Jabado, N, Bader, GD, Jones, SJM, Malkin, D, Marra, MA & Taylor, MD 2016, 'Divergent clonal selection dominates medulloblastoma at recurrence', Nature, vol. 529, no. 7586, pp. 351-357. https://doi.org/10.1038/nature16478

@article{b588deea1151422d9bcf1097b439cb5b,

title = "Divergent clonal selection dominates medulloblastoma at recurrence",

abstract = "The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.",

author = "Morrissy, {A. Sorana} and Livia Garzia and Shih, {David J H} and Scott Zuyderduyn and Xi Huang and Patryk Skowron and Marc Remke and Cavalli, {Florence M G} and Vijay Ramaswamy and Lindsay, {Patricia E.} and Salomeh Jelveh and Donovan, {Laura K.} and Xin Wang and Betty Luu and Kory Zayne and Yisu Li and Chelsea Mayoh and Nina Thiessen and Eloi Mercier and Mungall, {Karen L.} and Yusanne Ma and Kane Tse and Thomas Zeng and Karey Shumansky and Roth, {Andrew J L} and Sohrab Shah and Hamza Farooq and Noriyuki Kijima and Holgado, {Borja L.} and Lee, {John J Y} and Stuart Matan-Lithwick and Jessica Liu and Mack, {Stephen C.} and Alex Manno and Michealraj, {K. A.} and Carolina Nor and John Peacock and Lei Qin and Juri Reimand and Adi Rolider and Thompson, {Yuan Y.} and Xiaochong Wu and Trevor Pugh and Adrian Ally and Mikhail Bilenky and Butterfield, {Yaron S N} and Rebecca Carlsen and Young Cheng and Eric Chuah and Corbett, {Richard D.} and Noreen Dhalla and An He and Darlene Lee and Li, {Haiyan I.} and William Long and Michael Mayo and Patrick Plettner and Qian, {Jenny Q.} and Schein, {Jacqueline E.} and Angela Tam and Tina Wong and Inanc Birol and Yongjun Zhao and Faria, {Claudia C.} and Jos{\'e} Pimentel and Sofia Nunes and Tarek Shalaby and Michael Grotzer and Pollack, {Ian F.} and Hamilton, {Ronald L.} and Li, {Xiao Nan} and Bendel, {Anne E.} and Fults, {Daniel W.} and Walter, {Andrew W.} and Toshihiro Kumabe and Teiji Tominaga and Collins, {V. Peter} and Cho, {Yoon Jae} and Caitlin Hoffman and David Lyden and Wisoff, {Jeffrey H.} and Garvin, {James H.} and Stearns, {Duncan S.} and Luca Massimi and Ulrich Sch{\"u}ller and Jaroslav Sterba and Karel Zitterbart and Stephanie Puget and Olivier Ayrault and Dunn, {Sandra E.} and Tirapelli, {Daniela P C} and Carlotti, {Carlos G.} and Helen Wheeler and Hallahan, {Andrew R.} and Wendy Ingram and MacDonald, {Tobey J.} and Olson, {Jeffrey J.} and {Van Meir}, {Erwin G.} and Lee, {Ji Yeoun} and Wang, {Kyu Chang} and Kim, {Seung Ki} and Cho, {Byung Kyu} and Torsten Pietsch and Gudrun Fleischhack and Stephan Tippelt and Ra, {Young Shin} and Simon Bailey and Lindsey, {Janet C.} and Clifford, {Steven C.} and Eberhart, {Charles G.} and Cooper, {Michael K.} and Packer, {Roger J.} and Maura Massimino and Garre, {Maria Luisa} and Ute Bartels and Uri Tabori and Hawkins, {Cynthia E.} and Peter Dirks and Eric Bouffet and Rutka, {James T.} and Wechsler-Reya, {Robert J.} and Weiss, {William A.} and Collier, {Lara S.} and Dupuy, {Adam J.} and Andrey Korshunov and Jones, {David T W} and Marcel Kool and Northcott, {Paul A.} and Pfister, {Stefan M.} and Largaespada, {David A.} and Mungall, {Andrew J.} and Moore, {Richard A.} and Nada Jabado and Bader, {Gary D.} and Jones, {Steven J M} and David Malkin and Marra, {Marco A.} and Taylor, {Michael D.}",

note = "Funding Information: Acknowledgements The MAGIC project is financially supported by: Genome Canada, Genome BC, Terry Fox Research Institute, Ontario Institute for Cancer Research, Pediatric Oncology Group Ontario, Funds from {\textquoteleft}The Family of Kathleen Lorette{\textquoteright} and the Clark H. Smith Brain Tumour Centre, Montreal Children{\textquoteright}s Hospital Foundation, Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, B.R.A.I.N. Child, and BC Childhood Cancer Parents Association. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick{\textquoteright}s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by The Canadian Cancer Society Research Institute, The Garron Family Chair in Childhood Cancer Research, and grants from the Cure Search for Children{\textquoteright}s Cancer Foundation, the National Institutes of Health (R01CA148699 R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, Brainchild and The McLaughlin Centre at the University of Toronto. M.D.T. is also supported by the Swifty Foundation. L.G. was supported by the Davis M. Ferguson Memorial Fund at ABTA. Alex{\textquoteright}s Lemonade Stand Young Investigator Award supported V.R. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. This work was also supported by a Program Project Grant from the Terry Fox Research Institute, and a Grand Challenge Award from CureSearch for Children{\textquoteright}s Cancer. Additionally, this work was supported by the PedBrain Tumour Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). Funding by the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) to S.M.P., G.F. and T.P. The study was also financed by the Hungarian Brain Research Program Grant No. KTIA_13_NAP-A-V/3. and NAP-A-II/7. A.K. was supported by the J{\'a}nos Bolyai scholarship of the Hungarian Academy of Sciences. E.G.V.M. was supported by NIH R01 grants CA163722 and NS096236, and St. Baldrick{\textquoteright}s and Cure Childhood Cancer Foundations . We would like to acknowledge R. P. Hill (Ontario Cancer Institute), the Labatt Brain Tumour Research Centre Tumour and Tissue Repository, which is supported by B.R.A.I.N. Child and Megan{\textquoteright}s Walk. M.R. is supported by a fellowship from the Dr. Mildred Scheel Foundation for Cancer Research/ German Cancer Aid. F.M.G.C. is supported by the Stephen Buttrum Brain Tumour Research Fellowship, granted by Brain Tumour Foundation of Canada. V.R. is supported by a CIHR fellowship and an Alberta Innovates-Health Solutions Clinical Fellowship. We would like to thank the Toronto Centre for Phenogenomics for animal housing and veterinary support, and the Preclinical Core II and animal research facility at STTARR (Spatiotemporal Targeting and Amplification of Radiation Response) in Toronto for assistance with CT-guided radiation experiments. We would like to thank Z. Wang for technical help with IHC, S. Archer for technical writing and C. Smith for artwork. Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited. All rights reserved.",

year = "2016",

month = jan,

day = "21",

doi = "10.1038/nature16478",

language = "English (US)",

volume = "529",

pages = "351--357",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7586",

}

TY - JOUR

T1 - Divergent clonal selection dominates medulloblastoma at recurrence

AU - Morrissy, A. Sorana

AU - Garzia, Livia

AU - Shih, David J H

AU - Zuyderduyn, Scott

AU - Huang, Xi

AU - Skowron, Patryk

AU - Remke, Marc

AU - Cavalli, Florence M G

AU - Ramaswamy, Vijay

AU - Lindsay, Patricia E.

AU - Jelveh, Salomeh

AU - Donovan, Laura K.

AU - Wang, Xin

AU - Luu, Betty

AU - Zayne, Kory

AU - Li, Yisu

AU - Mayoh, Chelsea

AU - Thiessen, Nina

AU - Mercier, Eloi

AU - Mungall, Karen L.

AU - Ma, Yusanne

AU - Tse, Kane

AU - Zeng, Thomas

AU - Shumansky, Karey

AU - Roth, Andrew J L

AU - Shah, Sohrab

AU - Farooq, Hamza

AU - Kijima, Noriyuki

AU - Holgado, Borja L.

AU - Lee, John J Y

AU - Matan-Lithwick, Stuart

AU - Liu, Jessica

AU - Mack, Stephen C.

AU - Manno, Alex

AU - Michealraj, K. A.

AU - Nor, Carolina

AU - Peacock, John

AU - Qin, Lei

AU - Reimand, Juri

AU - Rolider, Adi

AU - Thompson, Yuan Y.

AU - Wu, Xiaochong

AU - Pugh, Trevor

AU - Ally, Adrian

AU - Bilenky, Mikhail

AU - Butterfield, Yaron S N

AU - Carlsen, Rebecca

AU - Cheng, Young

AU - Chuah, Eric

AU - Corbett, Richard D.

AU - Dhalla, Noreen

AU - He, An

AU - Lee, Darlene

AU - Li, Haiyan I.

AU - Long, William

AU - Mayo, Michael

AU - Plettner, Patrick

AU - Qian, Jenny Q.

AU - Schein, Jacqueline E.

AU - Tam, Angela

AU - Wong, Tina

AU - Birol, Inanc

AU - Zhao, Yongjun

AU - Faria, Claudia C.

AU - Pimentel, José

AU - Nunes, Sofia

AU - Shalaby, Tarek

AU - Grotzer, Michael

AU - Pollack, Ian F.

AU - Hamilton, Ronald L.

AU - Li, Xiao Nan

AU - Bendel, Anne E.

AU - Fults, Daniel W.

AU - Walter, Andrew W.

AU - Kumabe, Toshihiro

AU - Tominaga, Teiji

AU - Collins, V. Peter

AU - Cho, Yoon Jae

AU - Hoffman, Caitlin

AU - Lyden, David

AU - Wisoff, Jeffrey H.

AU - Garvin, James H.

AU - Stearns, Duncan S.

AU - Massimi, Luca

AU - Schüller, Ulrich

AU - Sterba, Jaroslav

AU - Zitterbart, Karel

AU - Puget, Stephanie

AU - Ayrault, Olivier

AU - Dunn, Sandra E.

AU - Tirapelli, Daniela P C

AU - Carlotti, Carlos G.

AU - Wheeler, Helen

AU - Hallahan, Andrew R.

AU - Ingram, Wendy

AU - MacDonald, Tobey J.

AU - Olson, Jeffrey J.

AU - Van Meir, Erwin G.

AU - Lee, Ji Yeoun

AU - Wang, Kyu Chang

AU - Kim, Seung Ki

AU - Cho, Byung Kyu

AU - Pietsch, Torsten

AU - Fleischhack, Gudrun

AU - Tippelt, Stephan

AU - Ra, Young Shin

AU - Bailey, Simon

AU - Lindsey, Janet C.

AU - Clifford, Steven C.

AU - Eberhart, Charles G.

AU - Cooper, Michael K.

AU - Packer, Roger J.

AU - Massimino, Maura

AU - Garre, Maria Luisa

AU - Bartels, Ute

AU - Tabori, Uri

AU - Hawkins, Cynthia E.

AU - Dirks, Peter

AU - Bouffet, Eric

AU - Rutka, James T.

AU - Wechsler-Reya, Robert J.

AU - Weiss, William A.

AU - Collier, Lara S.

AU - Dupuy, Adam J.

AU - Korshunov, Andrey

AU - Jones, David T W

AU - Kool, Marcel

AU - Northcott, Paul A.

AU - Pfister, Stefan M.

AU - Largaespada, David A.

AU - Mungall, Andrew J.

AU - Moore, Richard A.

AU - Jabado, Nada

AU - Bader, Gary D.

AU - Jones, Steven J M

AU - Malkin, David

AU - Marra, Marco A.

AU - Taylor, Michael D.

N1 - Funding Information: Acknowledgements The MAGIC project is financially supported by: Genome Canada, Genome BC, Terry Fox Research Institute, Ontario Institute for Cancer Research, Pediatric Oncology Group Ontario, Funds from ‘The Family of Kathleen Lorette’ and the Clark H. Smith Brain Tumour Centre, Montreal Children’s Hospital Foundation, Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, B.R.A.I.N. Child, and BC Childhood Cancer Parents Association. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by The Canadian Cancer Society Research Institute, The Garron Family Chair in Childhood Cancer Research, and grants from the Cure Search for Children’s Cancer Foundation, the National Institutes of Health (R01CA148699 R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, Brainchild and The McLaughlin Centre at the University of Toronto. M.D.T. is also supported by the Swifty Foundation. L.G. was supported by the Davis M. Ferguson Memorial Fund at ABTA. Alex’s Lemonade Stand Young Investigator Award supported V.R. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. This work was also supported by a Program Project Grant from the Terry Fox Research Institute, and a Grand Challenge Award from CureSearch for Children’s Cancer. Additionally, this work was supported by the PedBrain Tumour Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). Funding by the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) to S.M.P., G.F. and T.P. The study was also financed by the Hungarian Brain Research Program Grant No. KTIA_13_NAP-A-V/3. and NAP-A-II/7. A.K. was supported by the János Bolyai scholarship of the Hungarian Academy of Sciences. E.G.V.M. was supported by NIH R01 grants CA163722 and NS096236, and St. Baldrick’s and Cure Childhood Cancer Foundations . We would like to acknowledge R. P. Hill (Ontario Cancer Institute), the Labatt Brain Tumour Research Centre Tumour and Tissue Repository, which is supported by B.R.A.I.N. Child and Megan’s Walk. M.R. is supported by a fellowship from the Dr. Mildred Scheel Foundation for Cancer Research/ German Cancer Aid. F.M.G.C. is supported by the Stephen Buttrum Brain Tumour Research Fellowship, granted by Brain Tumour Foundation of Canada. V.R. is supported by a CIHR fellowship and an Alberta Innovates-Health Solutions Clinical Fellowship. We would like to thank the Toronto Centre for Phenogenomics for animal housing and veterinary support, and the Preclinical Core II and animal research facility at STTARR (Spatiotemporal Targeting and Amplification of Radiation Response) in Toronto for assistance with CT-guided radiation experiments. We would like to thank Z. Wang for technical help with IHC, S. Archer for technical writing and C. Smith for artwork. Publisher Copyright: © 2016 Macmillan Publishers Limited. All rights reserved.

PY - 2016/1/21

Y1 - 2016/1/21

N2 - The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

AB - The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

UR - http://www.scopus.com/inward/record.url?scp=84955506668&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955506668&partnerID=8YFLogxK

U2 - 10.1038/nature16478

DO - 10.1038/nature16478

M3 - Article

C2 - 26760213

AN - SCOPUS:84955506668

SN - 0028-0836

VL - 529

SP - 351

EP - 357

JO - Nature

JF - Nature

IS - 7586

ER -

Divergent clonal selection dominates medulloblastoma at recurrence

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