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The role of genetic and environmental factors in the aetiology of esophageal cancer
Thesis (PhD)--Stellenbosch University, 2021.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2021
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| _version_ | 1867614021336694784 |
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| access_status_str | Open Access |
| author | Simba, Hannah |
| author2 | Sewram, Vikash |
| author_browse | Sewram, Vikash Simba, Hannah |
| author_facet | Sewram, Vikash Simba, Hannah |
| author_sort | Simba, Hannah |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2021. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/123653 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:45:24.995Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/123653 The role of genetic and environmental factors in the aetiology of esophageal cancer Simba, Hannah Sewram, Vikash Kuivaniemi, Helena Tromp, Gerard Abnet, Christian Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Global Health. Health Systems and Public Health. esophageal cancer, esophageal squamous cell carcinoma, genetic association, meta-analysis, carcinogens, attributable risk, gene expression, microarray analysis UCTD Thesis (PhD)--Stellenbosch University, 2021. ENGLISH SUMMARY : Esophageal cancer (EC) is an aggressive cancer contributing an estimated 572,034 new cases and 508,585 deaths annually. Because no early detection programs exist, late presentation and high mortality are the rule. Prevalence rates are high in East Asia, Southern Europe, as well as in Eastern and Southern Africa. This peculiar distribution draws attention on the specificity of certain risk factors to particular regions. South Africa is a hotspot for EC; high prevalence has been reported in the Eastern Cape for the past five decades. Little research attention is given to EC in Africa; therefore, the epidemiology, as well as the genetic and environmental basis of EC is not well understood. The high incidence of EC, and the fatal nature of the disease, warrants a dedicated study to understand risk factors and pathobiology to facilitate strategies on prevention and screening. The aim of this study was to assess the role of genetic and environmental factors in the development of EC, and investigate the underlying molecular pathobiology using gene expression. Genetic variants associated with esophageal squamous cell carcinoma (ESCC) in African populations were assessed in 23 studies. Altogether, 25 variants in 20 genes were reported with a statistically significant association. In addition, eight studies identified somatic alterations in 17 genes and evidence of loss of heterozygosity, copy number variation, and microsatellite instability. This was the first genetic systematic review in African populations. A meta-analysis on 27 studies investigating environmental and lifestyle risk factors for ESCC (tobacco, alcohol use, combined tobacco and alcohol use, polycyclic aromatic hydrocarbon exposure, esophageal injury and fruit and vegetable consumption) was carried out. Adverse associations between ESCC risk and all the risk factors were found, whereas fruit and vegetable consumption showed a protective effect. The proportion of ESCC attributable to tobacco (17%), alcohol use (13%), combined tobacco and alcohol use (23%), polycyclic aromatic hydrocarbon exposure (5%), esophageal injury (17%) and fruit and vegetable consumption (-11%) were estimated using population attributable fraction analysis. This study was the most comprehensive systematic review and meta-analysis on African literature. Genes and pathways with differential mRNA expression were identified using datasets on ESCC, esophageal adenocarcinoma (EAC) and Barrett’s esophagus (BE) using the Rank Product Method, and gene set enrichment analysis (SetRank), with the Reactome Annotation Database. A total of 18 publicly available GEO mRNA expression datasets on 906 tissue samples, were analyzed. Overall, 1,107 upregulated genes and 1,537 downregulated genes were outputted for BE, EAC and ESCC. Significantly associated pathways included “Extracellular matrix organisation”, “Collagen chain trimerization”, “TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain”, and “Cyclin B2 mediated events”. Pathways not previously discussed or interpreted for EC in literature were identified, which warrant further investigation. These results highlight the multifactorial and complex etiology of EC. Comprehensive large-scale studies on the genetic basis and pathobiology of ESCC are still lacking in Africa. Understanding EC requires an integrated approach incorporating different study designs to assess both environmental and genetic factors of EC. AFRIKAANSE OPSOMMING : kanker (EK) is ‘n aggressiewe kanker wat ‘n benaderde 572034 nuwe gevalle en 508585 sterftes jaarliks bydra. Omdat geen vroeë waarnemingsprogram bestaan nie, is laat waarneming en hoë mortaliteit die reël. Die voorkomskoers is hoog in Oos-Asië, Suid-Europa en Oos- en Suidelike Afrika. Hierdie eienaardige verspreiding lig spesifieke risikofaktore in sekere gebiede uit. Suid-Afrika is ‘n knelgebied vir EK; ‘n hoë voorkomskoers is aangemeld in die Oos- Kaap gedurende die vorige vyf dekades. Min navorsingsaandag is gevestig op EK in Afrika; daarom word die epidemiologie, en die genetiese en omgewingsbasis van EK, nie goed begryp nie. Die hoë insidensie van EK en die dodelike geaardheid daarvan regverdig geöormerkte bestudering daarvan om die risikofaktore en patologiese biologie te verstaan en stategieë vir voorkoming en sifting te bewerkstellig. Die doel van hierdie studie was om die rol van genetiese faktore, omgewingsfaktore en die onderliggende patologiese biologie in die ontwikkel van EK te ondersoek, deur geenuitdrukkingsdata te gebruik. Genetiese variante wat geassosieer is met esofageale plaveiselepiteel karsinoom (EPEK) in Afrika-bevolkings, is in 23 studies bestudeer. Altesaam 25 variante in 20 gene is met statistiese beduidendheid gerapporteer. Daarby het agt studies ook somatiese veranderinge in 17 gene en bewyse van verlies van heterosigositeit, kopie aantal variasie en mikrosatelliet onstabiliteit gewys. Hierdie is die eerste genetiese sistematiese oorsig in Afrikabevolkings. ‘n Meta-analise van 27 studies wat omgewings- en leefstylrisikofaktore vir EPEK ondersoek het (tabak, alkoholverbruik, tabak- en alkoholverbruik, polisikliese aromatiese hidrokoolstofblootstelling, esofageale besering en groente en vrugte verbruik) is uitgevoer. Ongewenste assosiasies tussen EPEK risiko en al die risikofaktore is gevind, terwyl groente en vrugte verbruik ‘n beskermende effek getoon het. Die breukdeel van EPEK toegeken aan tabak (17%), alkoholverbruik (13%), tabak- en alkoholverbruik (23%), polisikliese aromatiese hidrokoolstof blootstelling (5%), esofageale besering (17%) en groente en vrugte verbruik (-11%) is bepaal deur bevolkingstoekenningsfraksie analise. Hierdie studie is die mees deeglike sistematiese oorsig en meta-analise nóg van Afrika literatuur. Gene en biologiese netwerke met differensiële bRNS uitdrukking is geïdentifiseer in EPEK, esofageale adenokarsinoom (EAK) en Barret se esofagus (BE) datastelle deur die rangorde produk metode te gebruik, tesame met geenversameling verrykingsanalise (SetRank), met die Reactome Annotation databasis. ‘n Totaal van 18 publieke beskikbare GEO bRNS geenuitdrukkingsdatastelle vir 906 weefselmonsters, is geanaliseer. In totaal is 1107 oorgereguleerde, en 1537 ondergereguleerde gene gevind vir BE, EAC en ESCC. Beduidende geassosieerde biologiese netwerke het “Ekstra-sellulêre matriks organisasie”, “Kollageenketting trimerisasie”, “TP53 reguleer transkripsie van verskeie addisionele seldood gene waarvan die spesifieke rolle in p53-afhanklike apoptose onseker bly”, en “Siklien B2- gemediëerde gebeurtenisse” ingesluit. Biologiese netwerke wat nie voorheen in EK literatuur bespreek of geïnterpreteer is nie, is gevind en verdere ondersoeke daarvan is geregverdig. Hierdie resultate lig die veelvuldige betrokke faktore en komplekse etiologie van EK, uit. Deeglike grootskaalse studies oor die genetiese basis en patologiese biologie van EPEK is steeds beperk in Afrika. ‘n Begrip van EK benodig ‘n geïntegreerde benadering wat verskillende studie ontwerpe insluit, om beide omgewings- en genetiese faktore te ondersoek. Doctoral 2021-09-03T12:47:07Z 2021-12-22T14:14:11Z 2021-09-03T12:47:07Z 2021-12-22T14:14:11Z 2021-12 Thesis http://hdl.handle.net/10019.1/123653 en_ZA Stellenbosch University xxx, 372 pages ; illustrations, includes annexures application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | esophageal cancer, esophageal squamous cell carcinoma, genetic association, meta-analysis, carcinogens, attributable risk, gene expression, microarray analysis UCTD Simba, Hannah The role of genetic and environmental factors in the aetiology of esophageal cancer |
| title | The role of genetic and environmental factors in the aetiology of esophageal cancer |
| title_full | The role of genetic and environmental factors in the aetiology of esophageal cancer |
| title_fullStr | The role of genetic and environmental factors in the aetiology of esophageal cancer |
| title_full_unstemmed | The role of genetic and environmental factors in the aetiology of esophageal cancer |
| title_short | The role of genetic and environmental factors in the aetiology of esophageal cancer |
| title_sort | role of genetic and environmental factors in the aetiology of esophageal cancer |
| topic | esophageal cancer, esophageal squamous cell carcinoma, genetic association, meta-analysis, carcinogens, attributable risk, gene expression, microarray analysis UCTD |
| url | http://hdl.handle.net/10019.1/123653 |
| work_keys_str_mv | AT simbahannah theroleofgeneticandenvironmentalfactorsintheaetiologyofesophagealcancer AT simbahannah roleofgeneticandenvironmentalfactorsintheaetiologyofesophagealcancer |