Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant <i>IDH1</i>

Tali Mazor(University of California, San Francisco), Charles Chesnelong(University of Calgary), Aleksandr Pankov(University of California, San Francisco), Llewellyn E. Jalbert(University of California, San Francisco), Chibo Hong(University of California, San Francisco), Josie Hayes(University of California, San Francisco), Ivan Smirnov(University of California, San Francisco), Roxanne Marshall(University of California, San Francisco), Camila Ferreira de Souza(Henry Ford Health System), Yaoqing Shen(Canada's Michael Smith Genome Sciences Centre), Pavithra Viswanath(University of California, San Francisco), Houtan Noushmehr(Henry Ford Health System), Sabrina M. Ronen(University of California, San Francisco), Steven J.M. Jones(University of British Columbia), Marco A. Marra(University of British Columbia), J. Gregory Cairncross(University of Calgary), Arie Perry(University of California, San Francisco), Sarah J. Nelson(University of California, San Francisco), Susan M. Chang(University of California, San Francisco), Andrew W. Bollen(University of California, San Francisco), Annette M. Molinaro(University of California, San Francisco), Henrik Bengtsson(University of California, San Francisco), Adam B. Olshen(University of California, San Francisco), Samuel Weiss(University of Calgary), Joanna J. Phillips(University of California, San Francisco), H. Artee Luchman(University of Calgary), J Costello(University of California, San Francisco)
Proceedings of the National Academy of Sciences
September 15, 2017
10.1073/pnas.1708914114
Cited by 140Open Access
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Abstract

Significance Identifying the drivers of tumorigenesis provides insight into mechanisms of transformation and can suggest novel therapeutic targets. IDH1 mutations in gliomas are one such promising target. Drivers of tumor initiation may be distinct from those at tumor recurrence, however. Here, we demonstrate that in a subset of initially IDH1 mutant gliomas IDH1 is deleted or amplified at recurrence, yielding a higher grade tumor with a reprogrammed epigenome. We also report systematic selection for cells with IDH1 CNA in vitro and in vivo. Thus, while IDH1 mutation likely initiates gliomagenesis, neither mutant IDH1 nor the oncometabolite 2HG that it produces are required at recurrence. These findings have important implications for emerging therapeutic strategies targeting mutant IDH1.

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