Sub-Saharan Sophageal Squamous Cell Carcinoma Molecular Analysis
Ontology highlight
ABSTRACT: Esophageal squamous cell carcinoma (ESCC) occurs as much as 20x more frequently in sub-Saharan Africa than Western countries. Through the UNC-Malawi project collaboration we obtained whole-exome matched tumor/normal and RNA sequencing of 59 ESCC from Malawi between 2011-2012. DNA analysis revealed similar mutations as other cohorts, while RNA analysis revealed three distinct subtypes. Mutational signature analysis revealed a pattern of mutation not previously reported in other cohorts or more broadly. Taken together this suggests the high prevalence of ESCC in the region is secondary to an as yet identified mutagen.
SECONDARY ACCESSION(S): PRJNA401208PRJNA401209
REPOSITORIES: dbGaP
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Project description:Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with one of the highest world incidences in the Eastern Cape region of South Africa. Several genome wide studies have been performed on ESCC cohorts from Asian countries, North America, Malawi and other parts of the world but none has been conducted on ESCC tumors from South Africa to date, where the molecular pathology and etiology of this disease remains unclear. We report here tumor associated copy number changes observed in 51 ESCC patients’ samples from the Eastern Cape province of South Africa. We extracted tumor DNA from 51 archived ESCC specimens and interrogated tumor associated DNA copy number changes using Affymetrix® 500K SNP array technology. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was applied to identify significant focal regions of gains and losses. Gains of the top recurrent cancer genes were validated by fluorescence in situ hybridization and their protein expression assessed by immunohistochemistry. Twenty-three significant focal gains were identified across samples. Gains involving the CCND1, MYC, EGFR and JAG1 loci recapitulated those described in studies on Asian and Malawian cohorts. The two most significant gains involved the chromosomal sub-bands 3q28, encompassing the TPRG1 gene and 11q13.3 including the CTTN, PPFIA1and SHANK2 genes. There was no significant homozygous loss and the most recurrent hemizygous deletion involved the B3GAT1 gene on chromosome11q25. Focal gains on 11q13.3 in 37% of cases (19/51), consistently involved CTTN and SHANK2 genes. Twelve of these cases (23,5%), had a broader region of gain that also included the CCND1, FGF19, FGF4 and FGF3 genes. SHANK2 and CTTN are co-amplified in several cancers, these proteins interact functionally together and are involved in cell motility. Immunohistochemistry confirmed both Shank2 (79%) and cortactin (69%) protein overexpression in samples with gains of these genes. In contrast, cyclin D1 (65%) was moderately expressed in samples with CCND1 DNA gain. This study reports copy number changes in a South African ESCC cohort and highlights similarities and differences with cohorts from Asia and Malawi. Our results strongly suggest a role for CTTN and SHANK2 in the pathogenesis of ESCC in South Africa.
2020-04-07 | GSE59105 | GEO
Project description:Our aim is to identify frequent genomic aberrations both in ESCC and esophageal dysplasia, and to discover important copy number-driving genes and microRNAs in ESCC. We carried out array-based comparative genomic hybridization (array CGH) on 59 ESCC resection samples and 16 dysplasia biopsy samples. Expression of genes at 11q13.3 was analyzed by real-time PCR and immunohistochemistry (IHC). Integrated analysis was performed to identify genes or microRNAs with copy number-expression correlations. Two group experiment, esophageal dysplasia vs. esophageal squamous cell carcinoma. Biological replicates: 16 dysplasias vs. 59 carcinomas
2013-04-29 | E-GEOD-46452 | biostudies-arrayexpress
Project description:<p>A genome-wide analysis of genetic structure, gene flow, and natural selection was conducted in populations in the endemic Burkitt lymphoma (eBL) belt in Ghana and Northern Uganda, both subject to a high incidence of falciparum malaria and eBL. These populations have different ethnolinguistic ancestries and are located 2400 miles apart in sub-Saharan Africa. We characterized genetic composition of these populations in the context of 22 additional African populations and present evidence for gene flow events that occurred in the last 3000 years, possibly related to regional migrations in Western Africa and major migrations involving Nilotic, Cushitic, and Bantu groups. The Ugandan population was comprised of 758 children (mean age ~7 years) from 17 Western Nilo-Saharan tribes. The current dataset includes 561 healthy children and 197 children with eBL from northern Uganda.</p>
| phs001705 | dbGaP
Project description:Burkitt lymphoma is the commonest cancer in children in Africa. We compared the gene expression profiles of African Burkitt lymphoma patients with those of cases presented in Western countries in both immunocompetent (sporadic Burkitt lymphoma) and HIV-infected patients (immunodeficiency associated Burkitt lymphoma). We used microarrays to detail the global programme of gene expression in different subtypes of Burkitt lymphoma.
2011-01-20 | GSE26673 | GEO
Project description:Sex-determining region Y- box 2 (Sox2) is a single-exon transcription factor essential for development and in cancer that has been shown to be overexpressed broadly in many cancers including multiple ovarian cancer subtypes. The objective of this study is to examine the effect of changing Sox2 expression under the conditions of anchorage independent growth that is known to drive the expression of survival genes. We compared genome wide gene expression profiles of the ovarian tumor cell line PA1 upon transient knockdown of Sox2 expression using siRNA and compared to negative silencer control siRNA cells. Cells grown in biological triplicates were transfected under steady state 2D growth conditions and then transferred to poly-hema coated plates to prevent attachment. After 72 hrs, RNA was collected from siSox2 and sicontrol cells followed by verification of reduction in Sox2 levels at the protein and RNA levels . Our analysis of the RNA seq results revealed 59 differentially expressed genes (DEG) between sicontrol and siSox2 cells (p-value ≤ 0.05) of which 52 were protein coding. Of the 59, 35 genes were upregulated in siSox2 and 24 genes were downregulated in the siSox2 cells . Gene set enrichment analysis of all the differentially expressed genes from the RNA-seq data revealed enrichment of 8 gene sets based on an FDR value <25% and included ‘hallmark of Apoptosis’, ‘TGF-β signaling’, and ‘Epithelial-Mesenchymal transition’ in siSox2 cells and hallmark interferon alpha response and interferon gamma response in sicontrol cells. Several transcription factors with prior established relationships to Sox2 including several PARP family members and TRIM family members were present in these gene sets.
2022-07-26 | GSE185932 | GEO
Project description:In this experiment, mice from 3 strains A/J, Balb C and C57Bl6 were infected with Trypanosoma Congolense, IL1180 clone, African sleeping sickness, a disease which affects cattle in sub-saharan Africa. These mouse strains were chosen because they are a model for tolerance to infection in cattle, with A/J and Balb B being highly susceptible, and C57Bl6 being somewhat more tolerant to infection. Three tissues Kidney Liver and Spleen were harvested from cohorts at various timepoints: 0 (naive), 3, 7, 9 and 17 days post infection. Each condition thus comprises: Time, Tissue, Strain. For each condition, RNA extracts from individuals were pooled (5 per pool) prior to hybridisation.
2007-08-21 | E-MEXP-1190 | biostudies-arrayexpress
Project description:<h4><strong>OBJECTIVE:</strong> Emerging evidence suggests that glucose depletion (GD)-induced cell death depends on system Xc-, a glutamate/cystine antiporter extensively studied in ferroptosis. However, the underlying mechanism remains debated. Our study confirmed the correlation between system Xc- and GD-induced cell death and provided a strategic treatment for oral squamous cell carcinoma (OSCC).</h4><p><strong>METHODS:</strong> qPCR and Western blotting were performed to detect changes in xCT and CD98 expression after glucose withdrawal. Then, the cell viability of OSCCs under the indicated conditions was measured. To identify the GD-responsible transcriptional factors of SLC7A11, we performed a luciferase reporter assay and a ChIP assay. Further, metabolomics was conducted to identify changes in metabolites. Finally, mitochondrial function and ATP production were evaluated using the seahorse assay, and NADP+/NADPH dynamics were measured using a NADP+/NADPH kit.</p><p><strong>RESULTS:</strong> In OSCCs, system Xc- promoted GD-induced cell death by increasing glutamate consumption, which promoted NADPH exhaustion and TCA blockade. Moreover, GD-induced xCT upregulation was governed by the p-eIF2α/ATF4 axis.</p><h4><strong>CONCLUSIONS:</strong> System Xc- overexpression compromised the metabolic flexibility of OSCC under GD conditions, and thus, glucose starvation therapy is effective for killing OSCC cells.</h4>
2024-01-16 | MTBLS5358 | MetaboLights
Project description:Zika virus (ZIKV) is a mosquito-transmitted positive-sense RNA virus in the family Flaviviridae. ZIKV infections are associated with neurodevelopmental deficiencies termed Congenital Zika Syndrome. ZIKV strains are grouped into three phylogenetic lineages: East African, West African, and Asian, which contains the American lineage. RNA virus genomes exist as genetically-related sequences. The heterogeneity of these viral populations is implicated in viral fitness, and genome diversity is correlated to virulence. This study examines genetic diversity of representative ZIKV strains from all lineages utilizing next generation sequencing (NGS). Inter-lineage diversity results indicate that ZIKV lineages differ broadly from each other; however, intra-lineage comparisons of American ZIKV strains isolated from human serum or placenta show differences in diversity when compared to ZIKVs from Asia and West Africa. This study describes the first comprehensive NGS analysis of all ZIKV lineages and posits that sub-consensus-level diversity may provide a framework for understanding ZIKV fitness during infection.
2018-12-31 | E-MTAB-5945 | biostudies-arrayexpress
Project description:We sought to determine how gene expression changes during the first two years of HIV-1 infection among participants from HIV-1 serodiscordant couple cohorts from sub-Saharan Africa. This study included whole blood samples from 26 participants who did not have HIV-1 at study enrollment, had a steady sexual relationship with a partner with HIV-1 and acquired HIV-1 during follow-up. Most participants had samples from before and after infection.
2023-03-10 | GSE195434 | GEO
Project description:Flis2015 - Plant clock gene circuit
(P2011.1.2 PLM_71 ver 1)
This model is described in the article:
Defining the robust
behaviour of the plant clock gene circuit with absolute RNA
timeseries and open infrastructure.
Flis A, Fernández AP, Zielinski
T, Mengin V, Sulpice R, Stratford K, Hume A, Pokhilko A, Southern
MM, Seaton DD, McWatters HG, Stitt M, Halliday KJ, Millar
AJ.
Open Biol 2015 Oct; 5(10):
Abstract:
Our understanding of the complex, transcriptional feedback
loops in the circadian clock mechanism has depended upon
quantitative, timeseries data from disparate sources. We
measure clock gene RNA profiles in Arabidopsis thaliana
seedlings, grown with or without exogenous sucrose, or in
soil-grown plants and in wild-type and mutant backgrounds. The
RNA profiles were strikingly robust across the experimental
conditions, so current mathematical models are likely to be
broadly applicable in leaf tissue. In addition to providing
reference data, unexpected behaviours included co-expression of
PRR9 and ELF4, and regulation of PRR5 by GI. Absolute RNA
quantification revealed low levels of PRR9 transcripts (peak
approx. 50 copies cell(-1)) compared with other clock genes,
and threefold higher levels of LHY RNA (more than 1500 copies
cell(-1)) than of its close relative CCA1. The data are
disseminated from BioDare, an online repository for focused
timeseries data, which is expected to benefit mechanistic
modelling. One data subset successfully constrained clock gene
expression in a complex model, using publicly available
software on parallel computers, without expert tuning or
programming. We outline the empirical and mathematical
justification for data aggregation in understanding highly
interconnected, dynamic networks such as the clock, and the
observed design constraints on the resources required to make
this approach widely accessible.
cL_m_degr, param m1, modified to ensure light rate > dark rate.
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2024-09-02 | BIOMD0000000597 | BioModels