scholarly journals NUTM1-Rearranged Neoplasms: A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations: An Updated Review

2021 ◽  
Author(s):  
Wenyi Luo ◽  
Todd Stevens ◽  
Phillip Stafford ◽  
Markku Miettinen ◽  
Zoran Gatalica ◽  
...  
Keyword(s):  
Hematologic Malignancies ◽  
Protein Product ◽  
Clinical Aspects ◽  
Chromosome 15 ◽  
Altered Expression ◽  
Molecular Alterations ◽  
Genome Wide ◽  
Bromodomain Proteins ◽  
Oncogenic Driver ◽  
Adnexal Tumors

Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-Sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update of NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.

scholarly journals NUTM1-Rearranged Neoplasms: A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations: An Updated Review

2021 ◽  
Vol 28 (6) ◽  
pp. 4485-4503
Author(s):  
Wenyi Luo ◽  
Todd M. Stevens ◽  
Phillip Stafford ◽  
Markku Miettinen ◽  
Zoran Gatalica ◽  
...  
Keyword(s):  
Hematologic Malignancies ◽  
Protein Product ◽  
Clinical Aspects ◽  
Chromosome 15 ◽  
Altered Expression ◽  
Molecular Alterations ◽  
Genome Wide ◽  
Bromodomain Proteins ◽  
Oncogenic Driver ◽  
Adnexal Tumors

Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update on NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.

scholarly journals A Genome-Wide Analysis of Pathogenesis-Related Protein-1 (PR-1) Genes from Piper nigrum Reveals Its Critical Role during Phytophthora capsici Infection

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1007
Author(s):  
Divya Kattupalli ◽  
Asha Sreenivasan ◽  
Eppurathu Vasudevan Soniya
Keyword(s):  
Phytophthora Capsici ◽  
Regulatory Elements ◽  
Piper Nigrum ◽  
Binding Motif ◽  
Altered Expression ◽  
Genome Wide ◽  
A Genome ◽  
Pathogenesis Related Protein ◽  
Pathogenesis Related

Black pepper (Piper nigrum L.) is a prominent spice that is an indispensable ingredient in cuisine and traditional medicine. Phytophthora capsici, the causative agent of footrot disease, causes a drastic constraint in P. nigrum cultivation and productivity. To counterattack various biotic and abiotic stresses, plants employ a broad array of mechanisms that includes the accumulation of pathogenesis-related (PR) proteins. Through a genome-wide survey, eleven PR-1 genes that belong to a CAP superfamily protein with a caveolin-binding motif (CBM) and a CAP-derived peptide (CAPE) were identified from P. nigrum. Despite the critical functional domains, PnPR-1 homologs differ in their signal peptide motifs and core amino acid composition in the functional protein domains. The conserved motifs of PnPR-1 proteins were identified using MEME. Most of the PnPR-1 proteins were basic in nature. Secondary and 3D structure analyses of the PnPR-1 proteins were also predicted, which may be linked to a functional role in P. nigrum. The GO and KEGG functional annotations predicted their function in the defense responses of plant-pathogen interactions. Furthermore, a transcriptome-assisted FPKM analysis revealed PnPR-1 genes mapped to the P. nigrum-P. capsici interaction pathway. An altered expression pattern was detected for PnPR-1 transcripts among which a significant upregulation was noted for basic PnPR-1 genes such as CL10113.C1 and Unigene17664. The drastic variation in the transcript levels of CL10113.C1 was further validated through qRT-PCR and it showed a significant upregulation in infected leaf samples compared with the control. A subsequent analysis revealed the structural details, phylogenetic relationships, conserved sequence motifs and critical cis-regulatory elements of PnPR-1 genes. This is the first genome-wide study that identified the role of PR-1 genes during P. nigrum-P. capsici interactions. The detailed in silico experimental analysis revealed the vital role of PnPR-1 genes in regulating the first layer of defense towards a P. capsici infection in Panniyur-1 plants.

scholarly journals Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis

Gut ◽  
2021 ◽  
pp. gutjnl-2020-322983
Author(s):  
Benjamin Goeppert ◽  
Damian Stichel ◽  
Reka Toth ◽  
Sarah Fritzsche ◽  
Moritz Anton Loeffler ◽  
...  
Keyword(s):  
Treatment Options ◽  
Genetic Alterations ◽  
Integrative Analysis ◽  
Intermediate Form ◽  
Precursor Lesions ◽  
Molecular Alterations ◽  
Genome Wide ◽  
Cells Of Origin ◽  
Sample Set ◽  
Methylation Profiling

ObjectiveA detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options.DesignWe analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling.ResultsPatients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but ROBO2 mutations occurred exclusively in invasive CCA and CTNNB1 mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin.ConclusionIntegrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.

scholarly journals Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations

Blood ◽  
2012 ◽  
Vol 120 (10) ◽  
pp. 2076-2086 ◽  
Author(s):  
Britta Will ◽  
Li Zhou ◽  
Thomas O. Vogler ◽  
Susanna Ben-Neriah ◽  
Carolina Schinke ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Genetic Alterations ◽  
Fish Analysis ◽  
Exact Nature ◽  
Clinical Relapse ◽  
Hematopoietic Stem ◽  
Molecular Alterations ◽  
Genome Wide ◽  
Stem And Progenitor Cells ◽  
Specific Expansion

Abstract Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage−/CD34+/CD38−/CD90+) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% ± 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations.

scholarly journals Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells

2016 ◽  
Vol 38 (5) ◽  
pp. 375-383 ◽  
Author(s):  
Jessica J. DeWitt ◽  
Patrick M. Hecht ◽  
Nicole Grepo ◽  
Brent Wilkinson ◽  
Oleg V. Evgrafov ◽  
...  
Keyword(s):  
Immune Response ◽  
Chromatin Remodeling ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Multiple Comparisons ◽  
Neural Progenitor ◽  
Autism Spectrum ◽  
Biological Processes ◽  
Altered Expression ◽  
Genome Wide

The long noncoding RNA MSNP1AS (moesin pseudogene 1, antisense) is a functional element that was previously associated with autism spectrum disorder (ASD) with genome-wide significance. Expression of MSNP1AS was increased 12-fold in the cerebral cortex of individuals with ASD and 22-fold in individuals with a genome-wide significantly associated ASD genetic marker on chromosome 5p14.1. Overexpression of MSNP1AS in human neuronal cells caused decreased expression of moesin protein, which is involved in neuronal process stability. In this study, we hypothesize that MSNP1AS knockdown impacts global transcriptome levels. We transfected the human neural progenitor cell line SK- N-SH with constructs that caused a 50% suppression of MSNP1AS expression. After 24 h, cells were harvested for total RNA isolation. Strand-specific RNA sequencing analysis indicated altered expression of 1,352 genes, including altered expression of 318 genes following correction for multiple comparisons. Expression of the OAS2 gene was increased >150-fold, a result that was validated by quantitative PCR. Gene ontology analysis of the 318 genes with altered expression following correction for multiple comparisons indicated that upregulated genes were significantly enriched for genes involved in immune response, and downregulated genes were significantly enriched for genes involved in chromatin remodeling. These data indicate multiple transcriptional and translational functions of MSNP1AS that impact ASD-relevant biological processes. Chromatin remodeling and immune response are biological processes implicated by genes with rare mutations associated with ASD. Our data suggest that the functional elements implicated by association of common genetic variants impact the same biological processes, suggesting a possible shared common molecular pathway of ASD.

scholarly journals An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer

2020 ◽  
Author(s):  
Athea Vichas ◽  
Naomi T. Nkinsi ◽  
Amanda Riley ◽  
Phoebe C.R. Parrish ◽  
Fujiko Duke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Spindle Assembly Checkpoint ◽  
Hippo Pathway ◽  
Spindle Assembly ◽  
Human Lung Cancer ◽  
Precision Oncology ◽  
Cancer Driver ◽  
Molecular Alterations ◽  
Pathway Gene ◽  
Genome Wide

ABSTRACTAdvances in precision oncology have transformed cancer therapy from broadly-applied cytotoxic therapy to personalized treatments based on each tumor’s unique molecular alterations. Here we investigate the oncogene-specific dependencies conferred by lung cancer driver variants of KRAS, EGFR, and RIT1. Integrative analysis of genome-wide CRISPR screens in isogenic cell lines identified shared and unique vulnerabilities of each oncogene. The non-identical landscape of dependencies underscores the importance of genotype-guided therapies to maximize tumor responses. Combining genetic screening data with small molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. This sensitivity may be related to a novel role of RIT1 in mitosis; we find that oncogenic RIT1M90I alters mitotic timing via weakening of the spindle assembly checkpoint. In addition, we uncovered a specific cooperation of mutant RIT1 with loss of Hippo pathway genes. In human lung cancer, RIT1 mutations and amplifications frequently co-occur with loss of Hippo pathway gene expression. These results provide the first genome-wide atlas of oncogenic RIT1-cooperating factors and genetic dependencies and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.

Abstract P252: Loss of HMGB2 Induces Chromatin Remodeling and Hypertrophic Growth in Cardiomyocytes

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Sarah Franklin ◽  
Haodong Chen ◽  
Scherise Mitchell-Jordan ◽  
Shuxun Ren ◽  
Peipei Ping ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mass Spectrometry ◽  
Chromatin Remodeling ◽  
Nuclear Dna ◽  
Specific Pattern ◽  
Altered Expression ◽  
Hypertrophic Growth ◽  
Knock Down ◽  
Genome Wide ◽  
Chromatin Structural

Nuclear DNA is packaged around the octameric nucleosome core particle, constituting the basic building block of chromatin. Non-nucleosome chromatin structural molecules have been shown to induce higher order packaging of DNA into structurally compact and inactive heterochromatin, or loosely packed and active euchromatin. These chromatin remodeling events are thought to establish a cell type specific pattern of gene expression. During the development of cardiac hypertrophy and failure, genes normally only expressed during development are re-activated. While a number of transcription factors involved in these changes in fetal gene expression have been identified, the means for genome-wide structural remodeling of DNA are unknown. To identify factors controlling genomic plasticity in cardiomyocytes, we used mass spectrometry to quantify chromatin-associated proteins from cardiac nuclei during stages of hypertrophy and failure in the mouse. Adult mice were subjected to cardiac pressure overload by transverse aortic constriction. Chromatin was fractionated from cardiac nuclei and DNA-bound proteins were acid extracted and analyzed by mass spectrometry. We measured chromatin occupancy patterns for >300 proteins during distinct stages of heart failure. To explore the isoform specific roles of individual chromatin structural proteins, we used siRNA to knock-down expression of two high mobility group proteins (HMGB1 and 2) exhibiting altered expression in the hypertrophic heart. Loss of HMGB2 (but not HMGB1) induced robust hypertrophic growth in cardiomyocytes. qRT-PCR analyses demonstrated that HMGB2 is responsible for some but not all changes in the fetal gene program (ANF increased 150% and SERCA decreased 20%, whereas α- and β-MHC were unchanged). To further explore the endogenous regions of the genome under control of HMGB2 packing, we performed microarrays following HMGB2 knockdown. Hypertrophy or HMGB2 knock-down induced global chromatin remodeling conducive to gene expression, as measured by histone post-translational modifications and the ratio of core to linker histones. These studies reveal a novel role of HMGB2 to inhibit hypertrophic growth and provide insights into general principles for genome-wide chromatin remodeling.

A genome‐wide significant association on chromosome 15 for congenital entropion in Swiss White Alpine sheep

2020 ◽  
Vol 51 (2) ◽  
pp. 278-283
Author(s):  
N. Hirter ◽  
A. Letko ◽  
I. M. Häfliger ◽  
D. Becker ◽  
D. Greber ◽  
...  
Keyword(s):  
Chromosome 15 ◽  
Genome Wide ◽  
A Genome

Early deficits in olfaction are associated with structural and molecular alterations in the olfactory system of a Huntington disease mouse model

2020 ◽  
Vol 29 (13) ◽  
pp. 2134-2147
Author(s):  
M Laroche ◽  
M Lessard-Beaudoin ◽  
M Garcia-Miralles ◽  
C Kreidy ◽  
E Peachey ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Olfactory System ◽  
Piriform Cortex ◽  
Olfactory Dysfunction ◽  
Altered Expression ◽  
Neuronal Nuclei ◽  
Molecular Alterations ◽  
Cell Death Pathways ◽  
Structural Abnormalities

Abstract Olfactory dysfunction and altered neurogenesis are observed in several neurodegenerative disorders including Huntington disease (HD). These deficits occur early and correlate with a decline in global cognitive performance, depression and structural abnormalities of the olfactory system including the olfactory epithelium, bulb and cortices. However, the role of olfactory system dysfunction in the pathogenesis of HD remains poorly understood and the mechanisms underlying this dysfunction are unknown. We show that deficits in odour identification, discrimination and memory occur in HD individuals. Assessment of the olfactory system in an HD murine model demonstrates structural abnormalities in the olfactory bulb (OB) and piriform cortex, the primary cortical recipient of OB projections. Furthermore, a decrease in piriform neuronal counts and altered expression levels of neuronal nuclei and tyrosine hydroxylase in the OB are observed in the YAC128 HD model. Similar to the human HD condition, olfactory dysfunction is an early phenotype in the YAC128 mice and concurrent with caspase activation in the murine HD OB. These data provide a link between the structural olfactory brain region atrophy and olfactory dysfunction in HD and suggest that cell proliferation and cell death pathways are compromised and may contribute to the olfactory deficits in HD.

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