Molecular landscape of pediatric diffuse intrinsic pontine gliomas: about 22 cases

Targeting Mutant PPM1D Sensitizes Diffuse Intrinsic Pontine Glioma Cells to the PARP Inhibitor Olaparib

“…Integrated genetic profiling of DIPGs has identified Histone H3 mutations (H3 K27M ) in genes encoding histone H3.3 (H3F3A, 65%) or H3.1 (HIST1H3B, 25%) and several other recurrent alterations that may serve as promising therapeutic targets for DIPGs (3)(4)(5)(6). Our laboratory and others identified recurrent mutations in the gene encoding protein phosphatase 1D, PPM1D, in 9-23% of DIPGs (4,(7)(8)(9). PPM1D mutations have been shown to cooccur with Histone H3 mutations (H3 K27M ) and are generally found to be mutually exclusive to tumor suppressor protein 53 (TP53)-inactivating mutations, but two cases displayed cooccurrence of a PPM1D mutation and TP53 mutation (likely subclonal) have also been reported in DIPGs (4,7,8,10,11).…”

Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas

“…Another direction for combinatorial treatments explores mutations that coexist with the H3K27M substitution in pHGGs. As an example, mutations in the PPM1D gene were identified in approximately 9–23% of DIPG samples and mostly co-occur with the H3K27M oncohistone ( Taylor et al, 2014 ; Wu et al, 2014 ; Zhang et al, 2014 ; El Ayoubi et al, 2017 ). PPM1D encodes a phosphatase responsible for dephosphorylation of multiple proteins involved in DNA damage response and DNA repair pathways ( Deng et al, 2020 ).…”