MassIVE MSV000088404

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PPM1D mutations are oncogenic drivers of de novo Diffuse Midline Glioma formation

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Description

Khadka P, Reitman ZJ, Lu S, Buchan G, Gionet G, Dubois F, Carvalho DM, Shih J, Zhang S, Greenwald N, Zack T, Shapira O, Pelton K, Hartley R, Bear H, Georgis Y, Jarmale S, Melanson R, Bonano K, Schoolcraft K, Miller PG, Condurat AL, Gonzalez E, Qian K, Morin E, Langhnoja J, Lupien L, Rendo V, Digiacomo J, Wang D, Zhou K, Kumbhani R, Guerra-Garcia ME, Sinai CE, Becker S, Schneider R, Vogelzang J, Krug K, Babur O, Goodale A, Abid T, Kalani Z, Piccioni F, Beroukhim R, Perskey N, Root D, Carcaboso AM, Ebert BL, Fuller C, Kieran MW, Jones C, Keshishian H, Ligon KL, Carr SA, Phoenix TN, and Bandopadhayay P. 2021. The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genomes sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of novel DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we applied integrative phosphoproteomic and functional genomics assays and found that the oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition. [doi:10.25345/C5HG4H] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: phosphorylation ; TMT

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Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser
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