p16 Loss and E2F/cell cycle deregulation in infant posterior fossa ependymoma

Abstract

Background Posterior fossa (PF) ependymomas (EPNs) in infants less than 1 year of age (iEPN-PF) have a poorer clinical outcome than EPNs in older children. While radiation therapy is the standard of care for the latter, it is withheld in infants to avoid neurotoxicity to immature brain. It is unknown whether the adverse outcome in iEPN-PFs is due to treatment differences or aggressive biology. We examined this question using molecular profiling. Methods Six anaplastic iEPN-PFs were subjected to transcriptomic analysis and FISH for p16 loss and gains of 1q, and compared with anaplastic PF EPNs from older children. Results were validated by immunohistochemistry (IHC). Results All six iEPN-PFs were grouped within EPN PF subgroup A (PFA). E2F targets and G2M checkpoint were identified as the most enriched gene sets in iEPN-PF, which was validated in a larger independent cohort. Accordingly, MIB-1 IHC demonstrated a higher mitotic rate in iEPN-PFs than noninfant anaplastic EPN PFA. Genetic and protein analyses demonstrated that p16 loss and low p16 protein expression is a hallmark of iEPN-PF, and that none harbored 1q gains. Kaplan–Meier analysis confirmed the poorer clinical outcome of the iEPN-PF cohort. Conclusions Biological differences, characterized by loss of p16 expression without gains of 1q in iEPN-PFs, as well as deregulated E2F target gene transcription, are indicative of deregulated p16-CDK4/6-pRB-E2F pathway activity. This may underlie the poor clinical outcome seen in this group of iEPN-PFs, rather than the withholding of radiation therapy. Results suggest a potential actionable therapy for iEPN-PF, namely cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.

Identification of a Distinct miRNA Regulatory Network in the Tumor Microenvironment of Transformed Mycosis Fungoides

“…In this study, we identified the upregulated miR-related signaling network in LCT-MF including ICOS-ICOSL signaling, PD1-PDL1 signaling, NF-κB signaling, E2F transcription, and molecular mechanisms of cancer pathways. Although these pathways have been consistent with previous studies in MF, other specific pathways of LCT-MF in this analysis, such as E2F transcription, have not been previously reported and are worthwhile to explore, as the interaction of malignant cells with E2F, for one, promotes a microenvironment suitable for tumor cell growth, survival, and aggressiveness [ 29 , 30 ]. Among the downregulated miRs, the miR with the most statistically significant log FC was the hsa-miR-708.…”

p16 loss facilitate hydroquinone‐induced malignant transformation of TK6 cells through promoting cell proliferation and accelerating the cell cycle progression

“…32,33 Decreased expression of p16 in cell lines regulates the cell cycle via Rb and increases proliferation and oncogenic capacity. 34 Here, flow cytometry revealed that HQ chronic exposure or p16 lost promoted cell cycle from G 0 /G 1 to S and G 2 /M phases. Conversely, p16 overexpression inhibited the entry of HQ-TK6 cell from G 0 /G 1 to S and G 2 /M phases (p < .01; Figure 5A).…”

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

“…CDK4 was likewise found overexpressed in EPN and associated with adverse outcomes [ 411 ]; accordingly, its inhibition restricted cell proliferation and reduced the expression of genes associated with the cell cycle and DNA repair ( CCNB1 , TOP2A , CDK2 , BRCA1 and RAD51 ), and induced morphological changes that culminated in cell death [ 412 ]. Considering EPN subgroups, De Almeida Magalhaes et al (2020) showed that CDK6 is overexpressed in ST-EPN-RELA tumors compared to other ST-EPN subgroups [ 413 ], even though others have suggested that the dysregulations of the p16-CDK4/6-pRB-E2F pathway might also compose the genetic background underlying the aggressive biology of posterior fossa EPN in infants less than 1 year old [ 414 ].…”