Biology subjects

Varn, F. S.

Publications and source records attributed to Varn, F. S..

9 recordsLinked to original sources

bioRxiv2025

TET CpG sequence context specific DNA demeth-ylation shapes progression of IDH-mutant gliomas

BackgroundTreatment decisions in IDH-mutant oligodendrogliomas are shaped by tumor aggressiveness, underscoring the need for objective grading of these malignant brain tumors. Material and MethodsWe collected 302 primary and recurrent resections from oligodendrogliomas and performed Ki-67 staining, proteomics and DNA methylation profiling. Results & conclusionDuring tumor progression, DNA methylation of oligodendrogliomas changed along a continuum. This continuum is linked to increased epigenetic aging, methylation of transcription factors and Ki-67+ cell density, and to large scale DNA demethylation. Demethylation was correlated with CpGs flanking sequences preferred by TET enzymes. We confirmed these findings in previously profiled astrocytomas, indicating IDH-mutant gliomas progress along a shared epigenetic axis. We developed an objective DNA methylation based prognostic continuous grading coefficient (CGC{psi}) that captured these changes and outperformed WHO grading for oligodendrogliomas. Our findings underscore the potential of DNA methylation-based grading to more accurately reflect tumor biology and inform clinical decision-making in IDH-mutant gliomas.

cancer biology↗

bioRxiv2023

IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy

Glioblastoma (GBM) brain tumours lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumours almost always fatally recur. Using RNAseq data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumours, we identified two responder subtypes based on therapy-driven changes in gene expression. In two thirds of patients a specific subset of genes is up-regulated from primary to recurrence (Up responders) and in one third the same genes are down-regulated (Down responders). Characterisation of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms. In Up responders treatment enriches for quiescent proneural GBM stem cells and differentiated neoplastic cells with increased neurotransmitter signalling, whereas Down responders commonly undergo therapy-driven mesenchymal transition. Stratifying GBM tumours by response subtype may lead to more effective treatment. In support of this, modulators of gamma aminobutyric acid (GABA) neurotransmitter signalling differentially sensitise Up and Down responder GBM models to standard treatment in vitro.

cancer biology↗

bioRxiv2022

GBMdeconvoluteR accurately infers proportions of neoplastic and immune cell populations from bulk glioblastoma transcriptomics data

The biological and clinical impact of neoplastic and immune cell type ratios in the glioblastoma (GBM) tumour microenvironment is being realised. Characterising and quantifying cell types within GBMs at scale will facilitate a better understanding of the association between the cellular landscape and tumour phenotypes or clinical correlates. This study aimed to develop a tool that can deconvolute immune and neoplastic cells within the GBM tumour microenvironment from bulk RNA sequencing data. We developed an IDH wild-type (IDHwt) GBM specific single immune cell reference dataset, from four independent studies, consisting of B cells, T cells, NK cells, microglia, tumour associated macrophages, monocytes, mast and DC cells. We used this alongside an existing neoplastic single cell-type dataset consisting of astrocyte-like, oligodendrocyte- and neuronal-progenitor like and mesenchymal GBM cancer cells to create both marker and gene signature matrix-based deconvolution tools. We then applied single-cell resolution imaging mass cytometry (IMC) to ten IDHwt GBM samples, five paired primary and recurrent tumours, in parallel with these tools to determine which performed best. Marker based gene expression deconvolution using GBM tissue specific markers, which we have packaged as GBMdeconvoluteR, gave the most accurate results. The correlation between immune cell quantification by IMC and by GBMdeconvoluteR for primary IDHwt GBM samples was 0.52 (Pearsons P=7.8x10-3) and between neoplastic cell quantification by IMC and by GBMdeconvoluteR was 0.75 (Pearsons P=1.2x10-3). We applied GBMdeconvoluteR to bulk GBM RNAseq data from The Cancer Genome Atlas (TCGA) and were able to recapitulate recent findings from multi-omics single cell studies with regards associations between mesenchymal GBM cancer cells and both lymphoid and myeloid cells. Furthermore, we were able to expand upon this to show that these associations are stronger in patients with worse prognosis. GBMdeconvoluteR is accessible online at https://gbmdeconvoluter.leeds.ac.uk. Key pointsGBMdeconvoluteR is a glioblastoma-specific cellular deconvolution tool. When applied to bulk GBM RNAseq data, it accurately quantifies the neoplastic and immune cells in that tumour. It is available online at https://gbmdeconvoluter.leeds.ac.uk

cancer biology↗

bioRxiv2021

The epigenetic evolution of gliomas is determined by their IDH1 mutation status and treatment regimen

Tumor adaptation or selection is thought to underlie therapy resistance of gliomas. To investigate the longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 143 matched initial and recurrent patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) gliomas. IDHwt gliomas showed a longitudinally stable epigenome with relatively low levels of global methylation, whereas the epigenome of IDHmut gliomas showed initial high levels genome-wide of DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. By integrating DNA methylation and gene expression data, adaptive changes of putative master regulators of the cell cycle and of differentiation were seen in IDHmut recurrent tumors. Furthermore, relapses of IDHmut tumors were accompanied by histological progression which in turn influenced survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment differed between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment for IDHmut gliomas. Our study provides one of the largest cohorts of paired glioma samples profiled with epigenomics, transcriptomics and genomics; and our results demonstrate that the treatment of IDHmut gliomas reshapes the epigenome towards an IDHwt-like phenotype. Accordingly, the prevalent practice of early genotoxic treatment in this patient population may need to be revisited.

genomics↗

bioRxiv2021

Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment

To interrogate the factors driving therapy resistance in diffuse glioma, we collected and analyzed RNA and/or DNA sequencing data from temporally separated tumor pairs of 292 adult patients with IDH-wild-type or IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions associated with an increase in proliferating stem-like malignant cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their malignant cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a specific myeloid cell state defined by unique ligand-receptor interactions with malignant cells. Collectively, our results uncover recurrence-associated changes that could be targetable to shape disease progression following initial diagnosis.

cancer biology↗

bioRxiv2020

CASCADES, a novel SOX2 super-enhancer associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a median survival of just over one year. The failure of available treatments to achieve remission in patients with GBM has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence; in fact, the property of "stemness" itself may be responsible for treatment resistance. In this study, we identify a novel lncRNA, Cancer stem cell associated distal enhancer of SOX2 (CASCADES) that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in IDH-wild type GBM and significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell- and cancer-specific manner. Bioinformatics analysis reveals that CASCADES functions as a super-enhancer associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs and represent a novel epigenetic and therapeutic target for disrupting the cancer stem cell compartment in GBM.

cancer biology↗

bioRxiv2020

Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response

Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. Our analyses support that somatic copy number alterations (SCNAs) promote epigenetic instability and that SCNAs largely precede epigenetic and transcriptomic diversification during glioma evolution. We confirmed the link between genetic and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response.

cancer biology↗

bioRxiv2019

Comparative molecular life history of spontaneous canine and human gliomas

Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole genome-, exome-, transcriptome-and methylation-sequencing of 81 canine gliomas, we found alterations shared between canine and human gliomas such as the receptor tyrosine kinases, p53 and cell cycle pathways, and IDH1 R132. Canine gliomas showed high similarity with human pediatric gliomas per robust aneuploidy, mutational rates, relative timing of mutations, and DNA methylation patterns. Our cross-species comparative genomic analysis provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations.\n\nSignificanceDiffuse gliomas are the most common malignant brain tumors, with high-grade tumors carrying a dismal prognosis. Preclinical models have proven themselves as poor predictors of clinical efficacy. Spontaneous glioma in dogs provides an attractive alternative model, because of their comparable tumor microenvironment and tumor life history. We determined the similarities and differences between human and canine gliomas through genomic profiling, and leveraged our datasets to identify conserved somatic drivers, mutational processes and temporal ordering of somatic glioma events across species. We show that canine gliomas resemble human gliomas at (epi-)genetic levels and are more reminiscent of pediatric than adult disease, thus rationalizing sporadic canine glioma as a preclinical model tailored to measuring treatment efficacies in patients with canine or human glioma.

cancer biology↗

bioRxiv2018

Genomic characterization of six virus-associated cancers identifies changes in the tumor microenvironment and altered genetic programming

Viruses affect approximately 20% of all human cancers and express immunogenic proteins that make these tumor types potent targets for immune checkpoint inhibitors. In this study, we apply computational tools to The Cancer Genome Atlas and other datasets to define how virus infection shapes the tumor microenvironment and genetic architecture of 6 virus-associated tumor types. Across cancers, the cellular composition of the tumor microenvironment varied based on viral status, with infected tumors often exhibiting increased infiltration of cytolytic cell types. Analyses of the infiltrating T cell receptor repertoire revealed that Epstein-Barr virus was associated with decreased diversity in multiple cancers, suggesting an antigen-driven immune response. Tissue-specific gene expression signatures capturing these virus-induced transcriptomic changes successfully predicted virus status in independent datasets and were associated with both immune- and proliferation-related features that were predictive of prognosis. The analyses presented suggest viruses have distinct effects in different tumors with implications for immunotherapy.

cancer biology↗