4. Electronic Theses and Dissertations (ETDs) - Faculties submissions
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Item Analysing RNA-sequence data for pancreatic ductal adenocarcinoma tissue samples to identify potential biomarkers(University of the Witwatersrand, Johannesburg, 2023-09) Jamal, Khadija Sanober; Kaur, MandeepPancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of pancreatic cancer and is the fourth leading cause of death with a five-year survival rate of less than 10%. Patients are asymptomatic until detection is observed at a metastatic stage, hence contributing massively towards the high mortality rate. This study was conducted to explore PDAC and its two main subtypes, the classical and basal-like subtype, in an in-depth level via bioinformatic analysis. Bioinformatics is a computational approach to evaluate biological data by analysing omics data including genomic expression and proteomic sequences. A workflow consisting of programmes and web-tools was used to analyse PDAC RNA-sequence data. The sample sets were grouped according to tumour, stage, and subtype. The workflow began with quality control using FastQC and Trimmomatic. Alignment of sequencing files and counts were done through HISAT2 and HTSeq. The main component of this workflow was differential gene expression analysis to identify differentially expressed genes (DEGs), statistically significant genes, per compared conditions. WGCNA was used for co-expression analysis to identify the hub genes involved in regulating the biological network. Lastly, in-silico validation was done by using available web tools to support the findings of this workflow. The identified tumour genes included S100A11, PKM, GPRC5A, LAMC2 and ITGA2, which may represent as universal biomarkers as sample extraction was performed from data generated from individuals belonging to 8 different countries. KRT13 and IL6 were identified in the advanced stage and their role in cancer progression have been explored in this current study. The basal-like subtype had CAV1, DCVLD2 and TGFB2 genes that contribute to treatment resistance. The common dysregulated genes in the basal-like subtype and advanced stage were analysed to evaluate the link between subtype and stage which included WNT3A, TP63, KRT13 and IGF2BP. Coexpression analysis revealed hub genes for tumour (KIF4A, SPAG5, RRM2 and AURKA), basal-like subtype (BUB1, DEPDC1 and KIF14) and classical-subtype (PTPRN and CAMK2B). Through a machine learning model, recall, precision and accuracy scores per sample conditions for the DEGs were all above 94%. These potential biomarkers all have significant roles in promoting cancer progression, aggression and resistance. Hence, these may serve as a less invasive screening method for PDAC as DEGs were classified based on tissue or blood (extracellular vesicle) biomarkers. However, further wet laboratory validation is required for these biomarkers.Item Evaluation of outcomes in patients with pancreatic cancer and Human Immunodeficiency Virus at Chris Hani Baragwanath Academic Hospital and the Donald Gordon Medical Centre, Johannesburg(2024) Wing, Jessica RobertaBackground: Cancers which are not associated with Acquired Immune Deficiency Syndrome (AIDS) are increasing in incidence and mortality in the HIV-positive population. Pancreatic cancer (PC) is projected to be the second most common cause of cancer-related death by 2030. No literature exists on patients with PC and concomitant human immunodeficiency virus (HIV) infection in South Africa (SA), which has the highest number of HIV-positive people in the world. Objectives: To compare the demographics, stage, histological grade of disease, and survival outcomes of HIV-positive compared to HIV-negative patients diagnosed with PC. Methods: Records of patients diagnosed with PC were collected from Chris Hani Baragwanath Academic Hospital (CHBAH) and the Wits Donald Gordon Medical Centre (DGMC) from the 1 st of January 2013 to the 31st of December 2018. A total of 240 patients’ records were obtained. Demographic, clinical, and survival data were collected. Results: There were predominantly black Africans (64.6%) and males (54.6%) in the study. Although overall survival between the HIV-positive and negative patients did not differ (p=0.051), the median time of survival from presentation was significantly shorter in the HIV-positive compared to the HIV-negative patients (2.1 months; IQR 1.2-6.0 vs. 4.7 months; IQR 1.6-13.0; p=0.017). The HIV-positive cohort presented at a significantly younger age compared to the negative cohort (54.6; ±9.6 vs 62.4; ±11.1; p=0.0001) and at a more advanced stage of disease (72.2% vs. 43.1%; p=0.017). No difference was found between the histological grade of PC in both cohorts (p=0.298). The median survival time for HIV-positive patients on therapy at presentation was significantly longer compared to patients who were not (3.0; IQR 1.3-7.8 vs 1.1 months; IQR 0.9-1.9; p=0.037). Overall survival in patients who underwent pancreaticoduodenectomy at Wits DGMC was shown to be higher compared CHBAH V (41.7% vs. 12.5%; p=0.049). The majority of the patients presented with regionally advanced (30.6%) and metastatic (50.3%) disease. Conclusion: This is the first study in SA to provide insight into the clinical disease profile and survival outcomes of HIV-positive patients diagnosed with PC. This study has shown that HIV-infected patients with PC have a specific disease profile. Therefore, testing for HIV infection should be included in the management of all patients with PC, a higher index of suspicion for cancer should be maintained in younger HIV-positive patients and initiation of Antiretroviral treatment (ART) must be timeous.