Biology subjects

Dorris, K.

Publications and source records attributed to Dorris, K..

3 recordsLinked to original sources

bioRxiv2026

hTERT Expression, Regulation, and Prognostic Significance in Pediatric Medulloblastoma

BackgroundTelomerase reactivation, a hallmark of many cancers, is associated with expression of its catalytic subunit, hTERT. However, the prognostic significance of telomere maintenance mechanisms in pediatric medulloblastoma remains poorly defined. MethodsIn this multi-institutional retrospective study of telomerase expression and hTERT regulation in newly diagnosed children with medulloblastoma, hTERT and MYC expression were assessed by qRT-PCR, normalized to non-neoplastic brain control samples. hTERT promoter methylation was analyzed using quantitative pyrosequencing and Illumina 450k methylation array. Cox proportional-hazard regression analyses evaluated the association of hTERT expression with progression-free survival (PFS) or overall survival (OS). Spearman correlation and Kruskal-Wallis tests correlated hTERT promoter methylation and expression and assessed variations among medulloblastoma subgroups, respectively. ResultsAmong 74 patients with available hTERT expression and outcome data, higher expression was associated with worse OS (HR=1.22, 95% CI: 1.01-1.47, p=0.036) and PFS (HR=1.17, 95% CI: 1.00-1.37, p=0.051) after adjusting for subgroup. Similar results were obtained when adjusting for metastatic status. Group 3 patients had the highest hTERT expression (p=0.001). Pyrosequencing data were available for 61 patients and 450k methylation array data for 292 patients. hTERT promoter was differentially methylated across subgroups with WNT followed by group 3 demonstrating the highest methylation on 450k (p<0.0001), findings that were confirmed by pyrosequencing. hTERT promoter methylation positively correlated with hTERT expression (Spearman correlation=0.42, p=0.02 by 450k and 0.34, p=0.007 by pyrosequencing). No significant correlation was observed between hTERT and MYC expression. ConclusionElevated hTERT expression is associated with worse PFS and OS in medulloblastoma across subgroups, supporting telomerase inhibition as a potential therapeutic strategy.

cancer biology↗

bioRxiv2021

Therapeutic reversal of prenatal pontine ID1 signaling in DIPG

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive brain tumor with rare survival beyond two years. This poor prognosis is largely due to the tumors highly infiltrative and invasive nature. Previous reports demonstrate upregulation of the transcription factor ID1 with H3K27M and ACVR1 mutations, but this has not been confirmed in human tumors or therapeutically targeted. We developed an in utero electroporation (IUE) murine H3K27M-driven tumor model, which demonstrates increased ID1 expression in H3K27M- and ACVR1-mutated tumor cells. In human tumors, elevated ID1 expression is associated with H3K27M/ACVR1-mutation, brainstem location, and reduced survival. The ID1 promoter demonstrates a similar active epigenetic state in H3K27M tumor cells and murine prenatal hindbrain cells. In the developing human brain, ID1 is expressed highest in oligo/astrocyte-precursor cells (OAPCs). These ID1+/SPARCL1+ cells share a transcriptional program with astrocyte-like (AC-like) DIPG cells, and demonstrate upregulation of gene sets involved with regulation of cell migration. Both genetic and pharmacologic [cannabidiol (CBD)] suppression of ID1 results in decreased DIPG cell invasion/migration in vitro and invasion/tumor growth in multiple in vivo models. CBD reduces proliferation through reactive oxygen species (ROS) production at low micromolar concentrations, which we found to be achievable in the murine brainstem. Further, pediatric high-grade glioma patients treated off-trial with CBD (n=15) demonstrate tumor ID1 reduction and improved overall survival compared to historical controls. Our study identifies that ID1 is upregulated in DIPG through reactivation of a developmental OAPC transcriptional state, and ID1-driven invasiveness of DIPG is therapeutically targetable with CBD. One Sentence SummaryThe transcription factor ID1 is upregulated in a subset of DIPG tumor cells, and ID1-driven invasiveness is therapeutically targetable with CBD.

cancer biology↗

bioRxiv2019

Comprehensive molecular characterization of pediatric treatment-induced high-grade glioma: A distinct entity despite disparate etiologies with defining molecular characteristics and potential therapeutic targets

Treatment-induced high-grade gliomas (TIHGGs) are an incurable late complication of cranial radiation therapy or combined radiation/chemotherapy used to treat pediatric cancer. We assembled a cohort of 33 TIHGGs from multiple institutions. The primary antecedent malignancies were medulloblastoma, acute lymphoblastic leukemia, astrocytoma, and ependymoma. We performed methylation profiling, RNA-seq, and genomic sequencing (whole-genome or whole-exome) on TIHGG samples. Methylation profiling revealed that TIHGGs cluster primarily with the pediatric receptor tyrosine kinase I subtype (26/31 samples). Common TIHGG copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, Ch. 4 loss, Ch. 6q loss, and Ch. 13 and Ch. 14 loss; focal alterations include PDGFRA and CDK4 gain and loss of CDKN2A and BCOR. Relative to de novo pediatric high-grade glioma (pHGG), BCOR loss (p=0.004) and CDKN2A loss (p=0.005) were significantly increased. Transcriptomic analysis identified two distinct TIHGG subgroups, one with a lesser mutation burden (0.12 mut/Mb), Ch. 1p loss/1q gain (5/6 samples), and stem cell characteristics, and one with a greater mutation burden (1.08 mut/Mb, p<0.0002), depletion of DNA repair pathways, and inflammatory characteristics. We observed increased chromothripsis in TIHGG versus pHGG (67% vs. 31%, p=0.036), which was associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. In vitro drug screening in one primary, patient-derived TIHGG cell line from each expression subgroup identified microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors as potentially effective therapies. This study provides a comprehensive molecular profile of TIHGG, including mechanistic insights to TIHGG oncogenesis, and identifies potentially effective therapeutic modalities for further investigation.

cancer biology↗