Faculty Bibliography
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47
Role of dysregulated cytokine signaling and bacterial triggers in the pathogenesis of Cutaneous T Cell Lymphoma
Cutaneous T cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome revealed a highly heterogeneous landscape of genetic perturbations and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease. Nonetheless, using data harvested from high-throughput transcriptional profiling allowed us to develop a reliable signature of this malignancy. Focusing on a key cytokine signaling pathway, previously implicated in CTCL pathogenesis, JAK/STAT signaling, we used conditional gene targeting to develop a fully penetrant small animal model of this disease that recapitulates many key features of mycosis fungoides, a common variant of CTCL. Using this mouse model, we demonstrate that T cell receptor engagement is critical for malignant transformation of the T lymphocytes and that progression of the disease is dependent on microbiota.
PMCID:5912980
PMID: 29128259
ISSN: 1523-1747
CID: 2785082
DNA methylation-based classification of central nervous system tumours
Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
PMCID:6093218
PMID: 29539639
ISSN: 1476-4687
CID: 2992882
Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling
Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile. Moreover, Atrx deficiency drives widespread shifts in chromatin accessibility, histone composition, and transcription in a distribution almost entirely restricted to genomic sites normally bound by the protein. Finally, direct gene targets of Atrx that mediate specific Atrx-deficient phenotypes in vitro exhibit similarly selective misexpression in ATRX-mutant human gliomas. These findings demonstrate that ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes in appropriate cellular and molecular contexts.
PMCID:5849741
PMID: 29535300
ISSN: 2041-1723
CID: 2992712
Cardiac arrhythmia and neuroexcitability gene variants in resected brain tissue from patients with sudden unexpected death in epilepsy (SUDEP)
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction. Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, includingARRB2,ITPR1,GABRR2,SSTR5,GRIK1,CTNAP2,GRM8,GNAI2andGRIK5. In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, includingKCNMB1,KCNIP1,DPP6,JUP,F2, andTUBA3D, which were not present in living epilepsy controls. Our data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.
PMCID:5869741
PMID: 29619247
ISSN: 2056-7944
CID: 3025312
RECURRENT HOMOZYGOUS DELETION OF DROSHA AND MICRODUPLICATION OF PDE4DIP CONTAINING THE ANCESTRAL DUF1220 DOMAIN IN PINEOBLASTOMA [Meeting Abstract]
ISI:000438339000189
ISSN: 1522-8517
CID: 5525552
ATRX DEFICIENCY IN GLIOMA CELLS OF ORIGIN PROMOTES DISEASE-DEFINING PHENOTYPES BY WAY OF GLOBAL EPIGENOMIC REMODELING [Meeting Abstract]
ISI:000415152502008
ISSN: 1523-5866
CID: 2802422
Analysis of molecular etiology and bacterial triggers of cutaneous T cell lymphoma [Meeting Abstract]
ISI:000406862400149
ISSN: 1523-1747
CID: 2667022
ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMAS: A CLINICOPATHOLOGIC AND MOLECULAR PROFILE [Meeting Abstract]
ISI:000398604103008
ISSN: 1523-5866
CID: 2545142
Clinical, Pathological and Molecular Characteristics of Infiltrating Astrocytomas of the Spinal cord [Meeting Abstract]
ISI:000377665000019
ISSN: 0022-3069
CID: 2687522
