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

Research output: Contribution to journalArticle

135 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)351-357
Number of pages7
JournalNature
Volume529
Issue number7586
DOIs
StatePublished - Jan 21 2016
Externally publishedYes

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Medulloblastoma
Recurrence
Clone Cells
Therapeutics
Image-Guided Radiotherapy
Genome
Neoplasms
Clinical Trials

ASJC Scopus subject areas

  • General

Cite this

Morrissy, A. S., Garzia, L., Shih, D. J. H., Zuyderduyn, S., Huang, X., Skowron, P., ... Taylor, M. D. (2016). Divergent clonal selection dominates medulloblastoma at recurrence. Nature, 529(7586), 351-357. https://doi.org/10.1038/nature16478

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

In: Nature, Vol. 529, No. 7586, 21.01.2016, p. 351-357.

Research output: Contribution to journalArticle

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, Y-J, 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
Morrissy AS, Garzia L, Shih DJH, Zuyderduyn S, Huang X, Skowron P et al. Divergent clonal selection dominates medulloblastoma at recurrence. Nature. 2016 Jan 21;529(7586):351-357. https://doi.org/10.1038/nature16478
Morrissy, A. Sorana ; Garzia, Livia ; Shih, David J.H. ; Zuyderduyn, Scott ; Huang, Xi ; Skowron, Patryk ; Remke, Marc ; Cavalli, Florence M.G. ; Ramaswamy, Vijay ; Lindsay, Patricia E. ; Jelveh, Salomeh ; Donovan, Laura K. ; Wang, Xin ; Luu, Betty ; Zayne, Kory ; Li, Yisu ; Mayoh, Chelsea ; Thiessen, Nina ; Mercier, Eloi ; Mungall, Karen L. ; Ma, Yusanne ; Tse, Kane ; Zeng, Thomas ; Shumansky, Karey ; Roth, Andrew J.L. ; Shah, Sohrab ; Farooq, Hamza ; Kijima, Noriyuki ; Holgado, Borja L. ; Lee, John J.Y. ; Matan-Lithwick, Stuart ; Liu, Jessica ; Mack, Stephen C. ; Manno, Alex ; Michealraj, K. A. ; Nor, Carolina ; Peacock, John ; Qin, Lei ; Reimand, Juri ; Rolider, Adi ; Thompson, Yuan Y. ; Wu, Xiaochong ; Pugh, Trevor ; Ally, Adrian ; Bilenky, Mikhail ; Butterfield, Yaron S.N. ; Carlsen, Rebecca ; Cheng, Young ; Chuah, Eric ; Corbett, Richard D. ; Dhalla, Noreen ; He, An ; Lee, Darlene ; Li, Haiyan I. ; Long, William ; Mayo, Michael ; Plettner, Patrick ; Qian, Jenny Q. ; Schein, Jacqueline E. ; Tam, Angela ; Wong, Tina ; Birol, Inanc ; Zhao, Yongjun ; Faria, Claudia C. ; Pimentel, José ; Nunes, Sofia ; Shalaby, Tarek ; Grotzer, Michael ; Pollack, Ian F. ; Hamilton, Ronald L. ; Li, Xiao Nan ; Bendel, Anne E. ; Fults, Daniel W. ; Walter, Andrew W. ; Kumabe, Toshihiro ; Tominaga, Teiji ; Collins, V. Peter ; Cho, Yoon-Jae ; Hoffman, Caitlin ; Lyden, David ; Wisoff, Jeffrey H. ; Garvin, James H. ; Stearns, Duncan S. ; Massimi, Luca ; Schüller, Ulrich ; Sterba, Jaroslav ; Zitterbart, Karel ; Puget, Stephanie ; Ayrault, Olivier ; Dunn, Sandra E. ; Tirapelli, Daniela P.C. ; Carlotti, Carlos G. ; Wheeler, Helen ; Hallahan, Andrew R. ; Ingram, Wendy ; MacDonald, Tobey J. ; Olson, Jeffrey J. ; Van Meir, Erwin G. ; Lee, Ji Yeoun ; Wang, Kyu Chang ; Kim, Seung Ki ; Cho, Byung Kyu ; Pietsch, Torsten ; Fleischhack, Gudrun ; Tippelt, Stephan ; Ra, Young Shin ; Bailey, Simon ; Lindsey, Janet C. ; Clifford, Steven C. ; Eberhart, Charles G. ; Cooper, Michael K. ; Packer, Roger J. ; Massimino, Maura ; Garre, Maria Luisa ; Bartels, Ute ; Tabori, Uri ; Hawkins, Cynthia E. ; Dirks, Peter ; Bouffet, Eric ; Rutka, James T. ; Wechsler-Reya, Robert J. ; Weiss, William A. ; Collier, Lara S. ; Dupuy, Adam J. ; Korshunov, Andrey ; Jones, David T.W. ; Kool, Marcel ; Northcott, Paul A. ; Pfister, Stefan M. ; Largaespada, David A. ; Mungall, Andrew J. ; Moore, Richard A. ; Jabado, Nada ; Bader, Gary D. ; Jones, Steven J.M. ; Malkin, David ; Marra, Marco A. ; Taylor, Michael D. / Divergent clonal selection dominates medulloblastoma at recurrence. In: Nature. 2016 ; Vol. 529, No. 7586. pp. 351-357.
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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 Yoon-Jae Cho 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.}",
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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.

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.

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