scholarly journals Identification of HOX Signatures Contributing to Oral Cancer Phenotype

2021 ◽  
Author(s):  
Kanaka Padam ◽  
Richard Morgan ◽  
Keith Hunter ◽  
Sanjiban Chakrabarty ◽  
Naveena Kumar ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Semantic Analysis ◽  
Tumor Development ◽  
Interaction Network ◽  
R Package ◽  
Tumor Formation ◽  
Phenotype Ontology ◽  
Cell Cycle Regulators ◽  
Human Phenotype ◽  
Cancer Phenotype

Abstract Purpose: Evolutionarily conserved homeobox-containing HOX genes as transcriptional regulators in the developmental specification of organisms is well known. The contribution of HOX genes involvement in oral cancer phenotype has yet to be fully ascertained.Methods: GEO datasets (GSE72627, GSE30784, GSE37991) were accessed and analyzed using GEO2R. TCGA-HNSC HTSeq-counts and clinical data were retrieved from the GDC portal for oral cavity neoplasms. Differential HOX gene expression was profiled using the DESeq2 R package with a log2 fold change cut-off (-1 and +1) and Benjamini-Hochberg p-adjusted value at <0.01. Gene set over-representation analysis and semantic analysis associated with the disease ontology were performed using ClusterProfiler R package and pathway over-representation analysis was performed using IMPaLa. HOX protein interaction network was constructed using the Pathfind R package. HOX phenotype associations were performed using Mammalian Phenotype Ontology, Human Phenotype Ontology, PhenGenI associations, Jensen tissues, and OMIM entries. Drug connectivity mapping was carried out with Dr. Insight R Package.Results: HOXB2 and HOXA5 genes were upregulated in oral dysplasia but silenced during tumor progression. Loss of HOXB2 expression was consistent through potentially malignant dysplastic oral lesions (PMOL) to primary tumor formation. HOXA10, HOXB7, HOXC6, HOXC10 and HOXD10 showed consistent upregulation from premalignancy to malignancy and were notably associated with risk factors. Overrepresentation analysis suggested HOXA10 was involved in the transcriptional misregulation leading to oral cancer phenotype. HOX subnetwork analysis showed crucial interactions with cell cycle regulators, growth responsive elements, and proto-oncogenes.Conclusion: Phenotype associations specific to the oral region involving HOX genes provide intrinsic cues to tumor development. The 5’ HOX genes were aberrantly deregulated which reflects their posterior prevalence during oral carcinogenesis.

scholarly journals p21 Is a Critical CDK2 Regulator Essential for Proliferation Control in Rb-deficient Cells

1998 ◽  
Vol 141 (2) ◽  
pp. 503-514 ◽  
Author(s):  
James Brugarolas ◽  
Roderick T. Bronson ◽  
Tyler Jacks
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Tumor Development ◽  
Tumor Formation ◽  
Cell Cycle Regulators ◽  
Loss Of Function ◽  
Extrinsic Factors ◽  
Cyclin Dependent Kinases ◽  
Inhibition Of Growth

Proliferation in mammalian cells is controlled primarily in the G1-phase of the cell cycle through the action of the G1 cyclin–dependent kinases, CDK4 and CDK2. To explore the mechanism of cellular response to extrinsic factors, specific loss of function mutations were generated in two negative regulators of G1 progression, p21 and pRB. Individually, these mutations were shown to have significant effects in G1 regulation, and when combined, Rb and p21 mutations caused more profound defects in G1. Moreover, cells deficient for pRB and p21 were uniquely capable of anchorage-independent growth. In contrast, combined absence of pRB and p21 function was not sufficient to overcome contact inhibition of growth nor for tumor formation in nude mice. Finally, animals with the genotype Rb+/−;p21−/− succumbed to tumors more rapidly than Rb+/− mice, suggesting that in certain contexts mutations in these two cell cycle regulators can cooperate in tumor development.

scholarly journals Representing glycophenotypes: semantic unification of glycobiology resources for disease discovery

Database ◽  
2019 ◽  
Vol 2019 ◽  
Author(s):  
Jean-Philippe F Gourdine ◽  
Matthew H Brush ◽  
Nicole A Vasilevsky ◽  
Kent Shefchek ◽  
Sebastian Köhler ◽  
...  
Keyword(s):  
Rare Diseases ◽  
Semantic Analysis ◽  
Model Organism ◽  
Disease Diagnosis ◽  
Knowledge Bases ◽  
Phenotype Ontology ◽  
Human Phenotype ◽  
Biological Ontologies ◽  
Phenotype Data ◽  
Structuring Knowledge

Abstract While abnormalities related to carbohydrates (glycans) are frequent for patients with rare and undiagnosed diseases as well as in many common diseases, these glycan-related phenotypes (glycophenotypes) are not well represented in knowledge bases (KBs). If glycan-related diseases were more robustly represented and curated with glycophenotypes, these could be used for molecular phenotyping to help to realize the goals of precision medicine. Diagnosis of rare diseases by computational cross-species comparison of genotype–phenotype data has been facilitated by leveraging ontological representations of clinical phenotypes, using Human Phenotype Ontology (HPO), and model organism ontologies such as Mammalian Phenotype Ontology (MP) in the context of the Monarch Initiative. In this article, we discuss the importance and complexity of glycobiology and review the structure of glycan-related content from existing KBs and biological ontologies. We show how semantically structuring knowledge about the annotation of glycophenotypes could enhance disease diagnosis, and propose a solution to integrate glycophenotypes and related diseases into the Unified Phenotype Ontology (uPheno), HPO, Monarch and other KBs. We encourage the community to practice good identifier hygiene for glycans in support of semantic analysis, and clinicians to add glycomics to their diagnostic analyses of rare diseases.

Predicting genes from phenotypes using Human Phenotype Ontology (HPO) terms

2021 ◽  
Vol 132 ◽  
pp. S149
Author(s):  
Anne Slavotinek ◽  
Hannah Prasad ◽  
Hannah Hoban ◽  
Tiffany Yip ◽  
Shannon Rego ◽  
...  
Keyword(s):  
Human Phenotype Ontology ◽  
Phenotype Ontology ◽  
Human Phenotype

Epigenetics in Clinical Management of Children and Adolescents with Brain Tumors

2017 ◽  
Vol 18 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Andres Morales La Madrid ◽  
Mark W. Kieran
Keyword(s):  
Nervous System ◽  
Brain Tumors ◽  
Children And Adolescents ◽  
Tumor Biology ◽  
Tumor Development ◽  
Integrated Approach ◽  
Cell Types ◽  
Pediatric Brain Tumors ◽  
Tumor Formation ◽  
Molecular Profile

Central nervous system (CNS) tumors represent the second most prevalent group of cancers in children and adolescents, yet account for the majority of childhood cancer-related deaths and considerable morbidity among survivors, due to high-intensity non-selective standard therapies delivered to immature nervous system structures undergoing development. These tumors arise at different ages –not infrequently very early in life-, in different locations and cellular contexts, have varied cell types of origin, and have heterogeneous responses to the “classic” current therapeutic approaches. Demographic, radiologic and morphological characterization have several limitations, putting into the “classic boxes” heterogeneous tumors that are diverse in their genetic and epigenetic background and that will likely behave biologically different. Given that, epigenetic disruption (i.e. DNA methylation, histone modification and chromatin remodeling) is a common feature identified more and more frequently in pediatric cancer, it is logical to speculate that interrogating epigenetic marks may help to further define the molecular profile, and therefore tumor biology, evolution and treatment of these tumors. An integrated approach that incorporates traditional features complemented with genetic and epigenenetic specific markers offers tremendous promise to “risk-group” stratification and better prognostication. Also, it will help unveil the key driver pathways for tumor formation and for the discovery of targeted therapy for neoplasms that appear in the developing brain, facilitating early identification of therapy responders and track accurately disease progression. In this paper, we reviewed the most representative pediatric brain tumors where epigenetic alterations have been identified as initiating or driving events in tumor development, maintenance or progression.

Cell proliferation is insufficient, but loss of tuberin is necessary, for chemically induced nephrocarcinogenicity

2002 ◽  
Vol 283 (2) ◽  
pp. F262-F270 ◽  
Author(s):  
Hae-Seong Yoon ◽  
Terrence J. Monks ◽  
Jeffrey I. Everitt ◽  
Cheryl L. Walker ◽  
Serrine S. Lau
Keyword(s):  
Cell Proliferation ◽  
Tissue Injury ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Tumor Formation ◽  
Renal Tumors ◽  
Outer Stripe ◽  
Acute Tissue Injury ◽  
Cell Cycle Deregulation ◽  
Erk Activity

Although 2,3,5-tris-(glutathion- S-yl)hydroquinone (TGHQ; 2.5 μmol/kg ip) markedly increased cell proliferation within the outer stripe of the outer medulla (OSOM) of the kidney in both wild-type ( Tsc2+/+ ) and mutant Eker rats ( Tsc2 EK/+), only TGHQ-treated Tsc2 EK/+ rats developed renal tumors, indicating that cell proliferation per se was not sufficient for tumor development. Tuberin expression was initially induced within the OSOM after TGHQ treatment but was lost within TGHQ-induced renal tumors. High extracellular signal-regulated kinase (ERK) activity occurred in the OSOM of Tsc2 EK/+ rats at 4 mo and in TGHQ-induced renal tumors. Cyclin D1 was also highly expressed in TGHQ-induced renal tumors. Reexpression of Tsc2 in tuberin-negative cells decreased ERK activity, consistent with the growth-suppressive effects of this tumor suppressor gene. Thus 1) stimulation of cell proliferation after toxicant insult is insufficient for tumor formation; 2) tuberin induction after acute tissue injury suggests that Tsc2 is an acute-phase response gene, limiting the proliferative response after injury; and 3) loss of Tsc2 gene function is associated with cell cycle deregulation.

scholarly journals BAX requires VDAC2 to mediate apoptosis and to limit tumor development

2018 ◽  
Author(s):  
Hui San Chin ◽  
Mark F. van Delft ◽  
Robert L. Ninnis ◽  
Mark X. Li ◽  
Iris K. L. Tan ◽  
...  
Keyword(s):  
Tumor Development ◽  
Anion Channel ◽  
Tumor Formation ◽  
Cytotoxic Action ◽  
Voltage Dependent Anion Channel ◽  
Genome Wide ◽  
Anti Cancer ◽  
Voltage Dependent ◽  
Genetic Deletion ◽  
First Time

AbstractIntrinsic apoptosis is critical for normal physiology including the prevention of tumor formation. BAX and BAK are essential for mediating this process and for the cytotoxic action of many anticancer drugs. BAX and BAK are thought to act in a functionally redundant manner and are considered to be regulated similarly. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as essential for BAX, but not BAK, to function. The genetic deletion of VDAC2 abrogated the association of BAX and BAK with mitochondrial complexes that contain VDAC1, VDAC2 and VDAC3. By disrupting its localization to mitochondria, BAX is rendered completely ineffective. Moreover, we defined an interface unique to VDAC2 that is required to drive BAX activity. Consequently, interfering with this interaction or deleting VDAC2 phenocopied the loss of BAX, including impairing the killing of tumor cells by anti-cancer agents such as the BCL-2 inhibitor venetoclax. Furthermore, the ability of BAX to prevent tumor formation was attenuated in the absence of VDAC2. Taken together, our studies show for the first time that BAX-mediated apoptosis, but not BAK-mediated apoptosis, is critically dependent on VDAC2, hence revealing the differential regulation of BAX and BAK.

TMOD-26. MYC OVEREXPRESSION AND SMARCA4 LOSS IN GRANULE CELL PRECURSORS COOPERATE TO DRIVE MEDULLOBLASTOMA FORMATION IN MICE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi221-vi221
Author(s):  
Carolin Göbel ◽  
Dörthe Holdhof ◽  
Melanie Schoof ◽  
Catena Kresbach ◽  
Ulrich Schüller
Keyword(s):  
Granule Cell ◽  
Clinical Course ◽  
Tumor Development ◽  
Tumor Formation ◽  
Human Group ◽  
Group 4 ◽  
Small Cohort ◽  
Group 3 ◽  
Granule Cell Precursors

Abstract Mutations in SMARCA4 are frequently identified in medulloblastoma, the most common pediatric malignant brain tumor. However, the functional significance of these mutations and their suitability as a therapeutic target remain largely unclear. Medulloblastomas are divided into 4 subgroups according to their localization, molecular biology, and clinical course: WNT, SHH, Group 3, and Group 4. Group 3 medulloblastomas are associated with the poorest outcome and frequently show amplifications of the oncogene MYC. Additionally, SMARCA4 is mutated in around 15 % of cases. The few mouse models developed for this entity so far all involve the overexpression of MYC, mostly in combination with other drivers. However, none of these models include alterations in Smarca4. In our approach, we combined an overexpression of MYC with a loss of SMARCA4 in granule cell precursors, which successfully induced tumor formation in mice. For this purpose, granule cell precursors were isolated from 7-day-old Math1-creER T2 ::Smarca4 fl/fl pups after tamoxifen induced loss of SMARCA4. MYC overexpression was achieved by lentiviral transduction and transduced cells were transplanted into immunodeficient CD1 nu/nu mice. Preliminary results within a small cohort showed tumor formation in 5/19 transplanted mice (26 %) after 6 months. Immunohistochemically, tumors all stained negative for SMARCA4. In a next step, additional cohorts will elucidate if tumor development is indeed accelerated by or even dependent on the loss of SMARCA4. Additionally, the neoplastic potential of tumor cells will be verified with the aid of secondary recipient mice. To evaluate to what extent the generated tumors are comparable to human Group 3 medulloblastomas, tumors will be extensively analyzed on a morphological, transcriptional, and epigenetic level. Altogether, we hope to establish a suitable mouse model for SMARCA4 mutated Group 3 medulloblastoma that will help to elucidate the role of SMARCA4 in tumor development and to identify new therapeutic targets.

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