Exome sequencing of lymphoma tumors developed in PPM1D transgenic mouse model after irradiation

Majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms. Our study show that frequent gain of the p53-regulating gene PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. A PPM1D transgenic mouse model develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1- and Pten-mutations, adenocarcinomas and PHOX2B-expressing neuroblastomas, therey establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.