Divergent clonal selection dominates medulloblastoma at recurrence
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| Authors: | 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, YS; 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, XC; Pugh, T; Ally, A; Bilenky, M; Butterfield, YSN; Carlsen, R; Cheng, Y; Chuah, E; Corbett, RD; Dhalla, N; He, A; Lee, D; Li, HYI; Long, W; Mayo, M; Plettner, P; Qian, JQ; Schein, JE; Tam, A; Wong, T; Birol, I; Zhao, YJ; 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; Schuller, 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 |
| Year: | 2016 |
| Journal: | Nature 529: 351-+ Article Link (DOI) |
| 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. |
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