Divergent clonal selection dominates medulloblastoma at recurrence
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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 Yao; Wu, Xiaochong; Pugh, Trevor J; 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 J; 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 B; 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. 351-7.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 Yao
AU - Wu, Xiaochong
AU - Pugh, Trevor J
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 J
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 B
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.
KW - Animals
KW - Cerebellar Neoplasms
KW - Clone Cells
KW - Craniospinal Irradiation
KW - DNA Mutational Analysis
KW - Disease Models, Animal
KW - Drosophila melanogaster
KW - Female
KW - Genome, Human
KW - Humans
KW - Male
KW - Medulloblastoma
KW - Mice
KW - Molecular Targeted Therapy
KW - Neoplasm Recurrence, Local
KW - Radiotherapy, Image-Guided
KW - Selection, Genetic
KW - Signal Transduction
KW - Xenograft Model Antitumor Assays
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/nature16478
DO - 10.1038/nature16478
M3 - SCORING: Journal article
C2 - 26760213
VL - 529
SP - 351
EP - 357
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7586
ER -