Divergent clonal selection dominates medulloblastoma at recurrence
| Authors |
MORRISSY A. Sorana GARZIA Livia SHIH J.H. David 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 JR James H. STEARNS Duncan S. MASSIMI Luca SCHÜLLER Ulrich ŠTĚRBA 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. MEIR Erwin G. Van 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. |
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| Year of publication | 2016 |
| Type | Article in Periodical |
| Magazine / Source | Nature |
| MU Faculty or unit | |
| Citation | |
| Doi | http://dx.doi.org/10.1038/nature16478 |
| Field | Oncology and hematology |
| Keywords | SUBGROUP MEDULLOBLASTOMA; LYMPHOBLASTIC-LEUKEMIA; CANCER EVOLUTION; SEQUENCING DATA; GENOME; MUTATIONS; HETEROGENEITY; DYNAMICS; IMPACT; CELLS |
| Description | 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. |