PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation
Prasidda Khadka, Zachary J. Reitman, Sophie D. Lu, Graham Buchan, Gabrielle Gionet, Frank Dubois, Diana Carvalho, Juliann Shih, Shu Zhang, Noah F. Greenwald, Travis Zack, Ofer Shapira, Kristine Pelton, Rachel Hartley, Heather Bear, Yohanna Georgis, Spandana Jarmale, Randy Melanson, Kevin Bonanno, Kathleen Schoolcraft, Peter G. Miller, Alexandra L. Condurat, Elizabeth M. Gonzalez, Kenin Qian, Eric Morin, Jaldeep Langhnoja, Leslie Lupien, Verónica Rendo, Jeromy J. Digiacomo, Dayle K. Wang, Kevin N. Zhou, Rushil Kumbhani, María E. Guerra García, Claire Sinai, Sarah Becker, Rachel Schneider, Jayne Vogelzang, Karsten Krug, Amy Goodale, Tanaz Abid, Zohra Kalani, Federica Piccioni, Rameen Beroukhim, Nicole S. Persky, David E. Root, Ángel M. Carcaboso, Benjamin L. Ebert, Christine Fuller, Özgün Babur, Mark W. Kieran, Chris Jones, Hasmik Keshishian, Keith L. Ligon, Steven A. Carr, Timothy N. Phoenix, Pratiti Bandopadhayay
Abstract
The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome 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 DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition.