A5034690648- Epigenetics and DNA Methylation
- Glioma Diagnosis and Treatment
- RNA Research and Splicing
- Neurogenesis and neuroplasticity mechanisms
- Diet and metabolism studies
- PARP inhibition in cancer therapy
- CAR-T cell therapy research
- Microtubule and mitosis dynamics
- ATP Synthase and ATPases Research
- Immunotherapy and Immune Responses
- Single-cell and spatial transcriptomics
- Mechanisms of cancer metastasis
- Cancer-related molecular mechanisms research
- RNA modifications and cancer
- Mitochondrial Function and Pathology
- MicroRNA in disease regulation
- Developmental Biology and Gene Regulation
- Plant Molecular Biology Research
- Molecular Biology Techniques and Applications
- Brain Tumor Detection and Classification
- Cell Image Analysis Techniques
- Cancer-related Molecular Pathways
- Genomics and Chromatin Dynamics
- Monoclonal and Polyclonal Antibodies Research
- Acute Myeloid Leukemia Research
Neurological Surgery
2023-2025
University of California, San Francisco
2023-2025
Duke University Hospital
2017-2023
Duke Medical Center
2014-2023
Duke University
2012-2021
Pediatric Brain Tumor Foundation
2012-2014
Abstract T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system’s recognition of cancer-specific antigens 1 . However, their efficacy is limited tumours with few somatic mutations and substantial intratumoural heterogeneity 2–4 Here we introduce a previously uncharacterized class tumour-wide public neoantigens originating from RNA splicing aberrations diverse types. We identified cell receptor clones capable recognizing targeting derived aberrant GNAS...
The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These utilize distinct genetic mechanisms telomere maintenance, either TERTp mutation leading to telomerase activation ATRX-mutation an alternative lengthening telomeres phenotype (ALT). However, about 20% lack alterations IDH. tumors, designated TERTpWT-IDHWT glioblastomas, do not have well-established biomarkers defined...
KMT2D (lysine (K)-specific methyltransferase 2D), formerly named MLL2 (myeloid/lymphoid or mixed-lineage leukemia 2, also known as ALR/MLL4), is a histone that plays an important role in regulating gene transcription. In particular, it targets H3 lysine 4 (H3K4), whose methylations serve activation mark. Recently, has emerged one of the most frequently mutated genes variety cancers and other human diseases, including lymphoma, medulloblastoma, gastric cancer, Kabuki syndrome. Mutations...
Brainstem gliomas are a heterogeneous group of tumors that encompass both benign cured with surgical resection and highly lethal cancers no efficacious therapies. We perform comprehensive study incorporating epigenetic genomic analyses on large cohort brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, PA-like, each associated unique clinical profiles. The majority within H3-Pons...
Abstract Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources expand the repertoire targetable (neo-)antigens improve outcomes. Accumulating evidence suggests that tumor-specific splicing (AS) could be an untapped reservoir antigens. this study, we investigated AS events focusing on those...
Myeloid/lymphoid or mixed-lineage leukemia ( MLL )-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. are frequently mutated human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 not well-understood. Specifically, little is regarding the extent global involvement expression mechanism underlying alterations driving tumorigenesis. Here we profile loci targeted by MLL2. A combinatorial analysis...
Inactivating mutations in the transcriptional repression factor Capicua (CIC) occur approximately 50% of human oligodendrogliomas, but mechanistic links to pathogenesis are unclear. To address this question, we generated Cic-deficient mice and oligodendroglioma cell models. Genetic deficiency resulted a partially penetrant embryonic or perinatal lethal phenotype, with production an aberrant proliferative neural population surviving animals. In vitro cultured stem cells derived from Cic...
IDH1 mutations occur in the majority of low-grade gliomas and lead to production oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand effects tumor-associated mutant (IDH1-R132H) on both neural stem cell (NSC) population brain tumorigenesis, genetically faithful lines mouse model systems were generated. Here, it is reported that NSCs expressing Idh1-R132H displayed reduced proliferation due p53-mediated cell-cycle arrest as well a decreased ability undergo neuronal differentiation. In...
Abstract Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss MTAP results profound epigenetic reprogramming characterized by hypomethylation PROM1/CD133–associated stem cell regulatory pathways. deficiency promotes glioma stem-like (GSC) formation with increased expression PROM1/CD133 and enhanced tumorigenicity GBM cells...
Abstract Intratumor heterogeneity and evolution underlie treatment failures but are poorly understood due to a limited number of tumor biopsies. In this study, we examine IDH mutant gliomas, utilizing 3D whole sampling approach exome sequencing (32 patients, 345 samples), along with RNAseq (12 the 32 88 samples). We investigate redefine intratumoral insertion/deletion (indel) single nucleotide variant (SNV) in driver genes on scale. suppressor capicua transcriptional repressor (CIC),...
// Genglin Jin 1 , Christopher J. Pirozzi Lee H. Chen Giselle Y. Lopez G. Duncan Jie Feng Ivan Spasojevic 2 Darell D. Bigner Yiping He and Hai Yan The Preston Robert Tisch Brain Tumor Center, Pediatric Foundation Institute, Department of Pathology, Clinical Pharmacology Laboratory, Duke Cancer Institute Medicine/Oncology University Medical Durham, North Carolina, USA Correspondence: Yan, email: Keywords : IDH1, cell survival Received July 27, 2012, Accepted August 04, Published 09, 2012...
T-cell-mediated immunotherapies are limited by the extent to which cancer-specific antigens homogenously expressed throughout a tumor. We reasoned that recurrent splicing aberrations in cancer represent potential source of tumor-wide and public neoantigens, test this possibility, we developed novel pipeline for identifying neojunctions uniformly within tumor across diverse types. Our analyses revealed multiple recur patients either exhibited intratumor heterogeneity or, some cases, were...
Diffuse intrinsic pontine glioma (DIPG) is an invariably fatal brain tumor occurring predominantly in children. Up to 90% of pediatric DIPGs harbor a somatic heterozygous mutation resulting the replacement lysine 27 with methionine (K27M) genes encoding histone H3.3 (H3F3A, 65%) or H3.1 (HIST1H3B, 25%). Several studies have also identified recurrent truncating mutations gene protein phosphatase 1D, PPM1D, 9%-23% DIPGs. Here, we sought investigate therapeutic potential targeting alone...
Mutations in isocitrate dehydrogenases 1 and 2 (IDH) occur the majority of World Health Organization grade II III gliomas. IDH1/2 active site mutations confer a neomorphic enzyme activity producing oncometabolite D-2-hydroxyglutarate (D-2HG), which generates glioma CpG island methylation phenotype (G-CIMP). While G-CIMP are commonly retained during tumor recurrence, recent work has uncovered losses IDH1 mutation subset secondary glioblastomas. Cooccurrence loss mutant allele with extensive...
Glioblastoma (GBM) is a lethal brain cancer exhibiting high levels of drug resistance, feature partially imparted by tumor cell stemness. Recent work shows that homozygous MTAP deletion, genetic alteration occurring in about half all GBMs, promotes stemness GBM cells. Exploiting loss-conferred deficiency purine salvage, we demonstrate blockade via treatment with L-Alanosine (ALA), an inhibitor de novo synthesis, attenuates MTAP-deficient This ALA-induced reduction mediated part compromised...
Diffuse intrinsic pontine gliomas (DIPGs) are high-grade tumors of the brainstem that often occur in children, with a median overall survival less than one year. Given fact DIPGs resistant to chemotherapy and not amenable surgical resection, it is imperative develop new therapeutic strategies for this deadly disease. The p53 pathway dysregulated by TP53 (~ 60%) or PPM1D gain-of-function mutations 30%) DIPG cases. suppress activity result tumorigenesis. While MDM2 major negative regulator...
Brain tumor-initiating cells (BTICs) and tumor cell plasticity promote glioblastoma (GBM) progression. Here, we demonstrate that clemastine, an over-the-counter drug for treating hay fever allergy symptoms, effectively attenuated the stemness suppressed propagation of primary BTIC cultures bearing PDGFRA amplification. These effects on BTICs were accompanied by altered gene expression profiling indicative their more differentiated states, resonating with activity clemastine in promoting...
Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter-and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources expand the repertoire targetable (neo-)antigens and improve outcomes. Accumulating evidence suggests that tumor-specific splicing (AS) could be an untapped reservoir neoantigens.
Abstract The concept that human cancer is in essence a genetic disease driven by gene mutations has been well established, yet its utilization functional studies of genes not fully explored. Here, we describe simple genetics-based approach can quickly and sensitively reveal the effect alteration interest on fate host cells within heterogeneous population, essentially monitoring selection associated with powers tumorigenesis. Using this approach, discovered loss-of-function TP53 promote...
Abstract BACKGROUND: Immunotherapy in gliomas is limited by intratumor heterogeneity (ITH) and low mutational burden. We developed a novel comprehensive silico pipeline for detecting tumor-specific splicing events (neojunctions), across multiple cancer types, we successfully identified new class of tumor-wide, public, alternatively spliced neoantigens (ASNs) that elicit CD8+ T-cell-mediated immune responses. METHODS: Our recurring public neojunctions expressed TCGA RNA-seq (positive sample...
Abstract Gliomas of the brainstem and surrounding regions are devastating brain tumors with highest mortality rates among all cancers. The locations make surgical resection difficult due to risk perioperative mortality. To understand genetics molecular biology this disease, we performed a comprehensive study, combining epigenetic genomic analyses clinical features on 126 gliomas, including 33 diffuse intrinsic pontine gliomas. Based DNA methylation data, identified four distinct clusters...
Abstract One striking theme emerging from recent findings in cancer genetics is that chromatin remodeling and histone methylation modifiers are frequently altered human cancers. Among these newly identified genes, one of the best examples gene encoding MLL2 (KMT2D, a.k.a. ALR/MLL4), a lysine methyltransferase plays an important role regulating transcription. Genetic alterations suggestive functional deficiency other genes same pathways common. The identification suggests potential new...
<p>Fig S3, proliferation assay. Fig S4 and S5, differentiation assay of Cic+/+ Cic-/- NSCs.</p>
<div>Abstract<p>Inactivating mutations in the transcriptional repression factor <i>Capicua</i> (<i>CIC</i>) occur approximately 50% of human oligodendrogliomas, but mechanistic links to pathogenesis are unclear. To address this question, we generated <i>Cic</i>-deficient mice and oligodendroglioma cell models. Genetic deficiency resulted a partially penetrant embryonic or perinatal lethal phenotype, with production an aberrant proliferative...