Doctoral Degrees (Health Systems and Public Health)

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Browsing Doctoral Degrees (Health Systems and Public Health) by browse.metadata.advisor "Abnet, Christian"

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    The role of genetic and environmental factors in the aetiology of esophageal cancer
    (Stellenbosch : Stellenbosch University, 2021-12) 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.
    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.