PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation.
Prasidda KhadkaZachary J ReitmanSophie LuGraham BuchanGabrielle GionetFrank DuboisDiana M CarvalhoJuliann ShihShu ZhangNoah F GreenwaldTravis ZackOfer ShapiraKristine PeltonRachel HartleyHeather BearYohanna GeorgisSpandana JarmaleRandy MelansonKevin BonannoKathleen SchoolcraftPeter G MillerAlexandra L ConduratElizabeth M GonzalezKenin QianEric MorinJaldeep LanghnojaLeslie E LupienVeronica RendoJeromy DigiacomoDayle K WangKevin Ning ZhouRushil KumbhaniMaria E Guerra GarciaClaire E SinaiSarah BeckerRachel SchneiderJayne VogelzangKarsten KrugAmy GoodaleTanaz AbidZohra KalaniFrederica PiccioniRameen BeroukhimNicole S PerskyDavid E RootAngel Montero CarcabosoBenjamin L EbertChristine FullerOzgun BaburMark W KieranChris JonesHasmik KeshishianKeith L LigonSteven A CarrTimothy N PhoenixPratiti BandopadhayayPublished in: Nature communications (2022)
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.