Frederick S. Varn
A5017653709- Cancer Immunotherapy and Biomarkers
- Glioma Diagnosis and Treatment
- Cancer Genomics and Diagnostics
- Ferroptosis and cancer prognosis
- Epigenetics and DNA Methylation
- Immune cells in cancer
- Single-cell and spatial transcriptomics
- RNA modifications and cancer
- Immunotherapy and Immune Responses
- Cancer-related molecular mechanisms research
- vaccines and immunoinformatics approaches
- Cancer, Hypoxia, and Metabolism
- Bladder and Urothelial Cancer Treatments
- MicroRNA in disease regulation
- Viral-associated cancers and disorders
- Radiomics and Machine Learning in Medical Imaging
- Urinary and Genital Oncology Studies
- Molecular Biology Techniques and Applications
- Immune Cell Function and Interaction
- Sarcoma Diagnosis and Treatment
- Cancer Cells and Metastasis
- RNA Research and Splicing
- Neuroinflammation and Neurodegeneration Mechanisms
- Gene expression and cancer classification
- Bioinformatics and Genomic Networks
Jackson Laboratory
2019-2024
UConn Health
2024
Dartmouth College
2015-2020
Tumor hypoxia is a negative prognostic factor that implicated in oncogenic signal activation, immune escape, and resistance to treatment. Identifying the mechanistic role of escape immune-checkpoint inhibitors may aid identification therapeutic targets. We others have shown V-domain Ig suppressor T-cell activation (VISTA), checkpoint regulator B7 family, highly expressed tumor microenvironment models primary human cancers. In this study, we show VISTA HIF1α activity are correlated cohort...
Abstract With the recent advent of immunotherapy, there is a critical need to understand immune cell interactions in tumor microenvironment both pan-cancer and tissue-specific contexts. Multidimensional datasets have enabled systematic approaches dissect these large numbers patients, furthering our understanding patient response solid tumors. Using an integrated approach, we inferred infiltration levels distinct subsets 23 types from The Cancer Genome Atlas. From quantities, constructed...
Abstract Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits 10–20% of patients. Here we perform genomic analysis tumor tissue from WHO grade IV patients acquired prior to intervention. We report that very low mutation burden is associated with longer after recombinant polio virotherapy or immune checkpoint blockade A relationship between and not observed cohorts naïve newly diagnosed Transcriptomic analyses reveal an inverse enrichment...
Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared molecular profiles of canine with those human pediatric adult to characterize evolutionarily conserved mammalian mutational processes gliomagenesis. Employing whole-genome, exome, transcriptome, methylation sequencing 83 gliomas, we found alterations shared such as receptor tyrosine kinases, TP53 cell-cycle pathways, IDH1 R132. Canine showed high similarity...
New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts subtype patients based on molecular profiles have failed direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification novel TME-specific subtypes could inform new immunotherapy strategies.A refined validated cell population (MCP) counter method was applied >800 patient tumours (GBM-MCP-counter). Specifically, partition around...
Abstract Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas response therapeutic pressure, we performed an epigenomic analysis 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) IDH-mutant (IDHmut) IDHwt showed a stable epigenome over time relatively low levels global methylation. The IDHmut high genome-wide DNA methylation that was progressively reduced similar those...
Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all neoplasms. Patients receive surgery and chemoradiotherapy but almost always fatally recur.
Drug resistance to approved systemic therapies in estrogen receptor–positive (ER+) breast cancer remains common. We hypothesized that factors present the human tumor microenvironment (TME) drive drug resistance. Screening of a library recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as potent mediator anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition ER+ cancer. Phosphoproteomic analyses identified ERK1/2 major output...
Abstract Background: Lung cancer is associated with the highest mortality rate of all types, and most common histologic subtype lung adenocarcinoma. To apply more effective therapeutic treatment, molecular markers that are able to predict recurrence risk patients adenocarcinoma critically needed. Mutations in TP53 tumor suppressor gene have been found approximately 50% cases, but presence a mutation does not always associate increased mortality. Methods: The Cancer Genome Atlas RNA...
Non-small cell lung cancer is one of the leading causes cancer-related death in world. Lung adenocarcinoma, most common type non-small cancer, has been well characterized as having a dense lymphocytic infiltrate, suggesting that immune system plays an active role shaping this cancer's growth and development. Despite these findings, our understanding how infiltrate affects patient prognosis its association with adenocarcinoma-specific clinical factors remains limited. To address questions, we...
Intra-tumor heterogeneity stems from genetic, epigenetic, functional, and environmental differences among tumor cells. A major source of genetic comes DNA sequence and/or whole chromosome focal copy number variations (CNVs). Whole CNVs are caused by chromosomal instability (CIN) that is defined a persistently high rate mis-segregation. Accordingly, CIN causes constantly changing karyotypes result in extensive cell-to-cell heterogeneity. How the influences gene expression individual cells...
Abstract Purpose: Tumor genomic features have been of particular interest because their potential impact on the tumor immune microenvironment and response to immunotherapy. Due substantial heterogeneity, an integrative approach incorporating diverse molecular is needed characterize immunologic underlying primary resistance immunotherapy for establishment novel predictive biomarkers. Experimental Design: We developed a pan-cancer deep machine learning model integrating mutation burden,...
The composition of the tumor immune microenvironment (TIME) is considered a key determinant patients' response to immunotherapy. mechanisms underlying TIME formation and development over time are poorly understood. Glioblastoma (GBM) lethal primary brain cancer for which there no curative treatments. GBMs immunologically heterogeneous impervious checkpoint blockade immunotherapies. Utilizing clinically relevant genetic mouse models GBM, we identified distinct landscapes associated with...
Abstract Transcriptional programmes active in haematopoietic cells enable a variety of functions including dedifferentiation, innate immunity and adaptive immunity. Understanding how these function the context cancer can provide valuable insights into host immune response, severity potential therapy response. Here we present method that uses transcriptomes over 200 murine cells, to infer lineage-specific activity human breast tumours. Correlating this with patient survival tumour purity...
Abstract Viruses affect approximately 20% of all human cancers and induce expression immunogenic viral oncoproteins that make these tumors potent targets for immune checkpoint inhibitors. In this study, we apply computational tools to The Cancer Genome Atlas (TCGA) other genomic datasets define how virus infection shapes the tumor microenvironment genetic architecture 6 virus-associated types. Across cancers, cellular composition varied by status, with virus-positive often exhibiting...
BACKGROUND. Immune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not tumor microenvironment (TME), or analyzed via biopsies.
Characterizing and quantifying cell types within glioblastoma (GBM) tumors at scale will facilitate a better understanding of the association between cellular landscape tumor phenotypes or clinical correlates. We aimed to develop tool that deconvolutes immune neoplastic cells GBM microenvironment from bulk RNA sequencing data.
Immune checkpoint inhibitors have shown great potential in treating solid tumors, inducing durable remission and prolonged survival time responders. Despite their promise, a large fraction of patients remains unresponsive to these treatments highlighting the need for biomarkers that can predict patient sensitivity. Pre-treatment gene expression profiles receiving immune recently become available, establishing new medium by which discover therapy response. In this study, we mined...