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.

Forkhead box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and pediatric cancer samples and found FOXR2 to be aberrantly upregulated in 70% of all cancer types and 8% of all individual tumors. The majority of tumors (78%) aberrantly expressed FOXR2 through a previously undescribed epigenetic mechanism that involves hypomethylation of a novel promoter, which was functionally validated as necessary for FOXR2 expression and proliferation in FOXR2-expressing cancer cells. FOXR2 promoted tumor growth across multiple cancer lineages and co-opted ETS family transcription circuits across cancers. Taken together, this study identifies FOXR2 as a potent and ubiquitous oncogene that is epigenetically activated across the majority of human cancers. The identification of hijacking of ETS transcription circuits by FOXR2 extends the mechanisms known to active ETS transcription factors and highlights how transcription factor families cooperate to enhance tumorigenesis. Significance: This work identifies a novel promoter that drives aberrant FOXR2 expression and delineates FOXR2 as a pan-cancer oncogene that specifically activates ETS transcriptional circuits across human cancers. See related commentary by Liu and Northcott, p. 2977

Aims We aimed to investigate the functional alterations, diagnostic utilization, and prognostic implication of carotid arterial deformations in subjects with cardiovascular risk factors and heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results Among 251 prospectively participants (mean age 66.0 ± 9.8 years, 65.7% female) in a single centre between December 2011 and September 2014, carotid artery deformations including circumferential strain (CCS)/strain rate and radial strain were analysed by two-dimensional speckle tracking. We further related these carotid artery deformation indices to HF biomarkers and cardiac structure and function by echocardiography and explored their prognostic values. Significant reductions of CCS, circumferential strain rate, and circumferential radial strain were observed across control (n = 52), high risk (n = 147), and HFpEF (n = 52) (trend P ≤ 0.001). Aging, hypertension, HFpEF, and higher pulse rate showed independent associations with reduced CCS by stepwise multivariate regressions (all P < 0.05). Higher CCS was inversely associated with better cardiac remodelling and functional indices, and lower multiple HF biomarkers (all P ≤ 0.005). After adjustment, higher CCS was independently associated with better global ventricular longitudinal strain/early diastolic strain rate, lower matrix metalloproteinase-2, and N-terminal propeptide of procollagen type III levels (adjusted coef: À0.08 and À19.9, all P < 0.05). During a median follow-up of 1406 days (interquartile range: 13421720 days), CCS less than 3.28% as a cutoff had markedly higher HF events [Harrell's C: 0.72, adjusted HR: 2.20 (95% confidence interval: 1.24, 3.16), P = 0.008]. CCS also showed significantly improved risk prediction for HF over global ventricular longitudinal strain (net reclassification index: 48%, P = 0.001; integrated discrimination improvement: 1.8%, P < 0.001). Conclusions Carotid artery deformations using two-dimensional speckle-tracking imaging showed novel mechanistic insights on functional arterial alterations reflecting coupled arterial-ventricular pathophysiology. Utilization of such measure may further provide additive prognostic value to advanced myocardial functional assessment.

A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames. To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future cancer genomics studies seeking to define new cancer targets.