E-Thesis 258 views 193 downloads
Using DNA damage in circulating blood cells as a biomarker for oesophageal adenocarcinoma risk / Kathryn Munn
Swansea University Author: Kathryn Munn
DOI (Published version): 10.23889/SUthesis.69525
Abstract
This thesis explored DNA damage in circulating blood cells as biomarkers for oesophageal adenocarcinoma (OAC) risk and treatment response using two assays: the cytokinesis-block micronucleus (CBMN) assay to measure lymphocyte micronucleus frequency (MN%) and the PIG-A mutation assay to assess PIG-A...
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Swansea, Wales, UK
2025
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| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Jenkins, Gareth ; Doak, Shareen |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa69525 |
| Abstract: |
This thesis explored DNA damage in circulating blood cells as biomarkers for oesophageal adenocarcinoma (OAC) risk and treatment response using two assays: the cytokinesis-block micronucleus (CBMN) assay to measure lymphocyte micronucleus frequency (MN%) and the PIG-A mutation assay to assess PIG-A mutant frequency (MF) in erythrocytes. Baseline MN% and PIG-A MF were significantly higher in OAC patients compared to those with gastroesophageal reflux disease (GORD), Barrett's oesophagus (BO), and healthy volunteers (HVs), aligning with previous studies linking increased MN% to cancer risk. The predictive value of PIG-A MF as a biomarker for overall cancer risk needs further investigation through large-scale studies. The study examined DNA damage response to cancer therapy, finding an increase in MN% and PIG-A MF during treatment, though the prediction of therapy response was inconclusive. Further investigation into the mechanisms behind the elevated MN% in OAC patients revealed complex interactions involving oxidative stress and inflammation. Pro-oxidant agents like hydrogen peroxide (H2O2) and deoxycholic acid (DCA) highlighted an adaptive response in patients, suggesting reduced sensitivity to subsequent in vitro DNA damage. Plasma from OAC patients also showed increased DNA damage induction in in vitro TK6 cells, indicating a potential genotoxic effect. Elevated levels of inflammatory markers such as IL-6 and IL-8 were associated with increased MN%, suggesting their potential role in biomonitoring OAC risk. The study examined the cGAS-STING pathway in vitro and ex vivo, finding slightly elevated levels of 2'3'-cGAMP and IFNβ in OAC patient plasma. This suggested a link to increased MN formation and highlighted the pathway's role in genetic instability and inflammation. Inhibition of the STING complex in TK6 cells prior to ionising radiation resulted in a slight but statistically non-significant reduction in MN%. Future research should focus on tissue-specific DNA damage and its correlation with blood-based biomarkers to assess their potential for predicting early cancer development. |
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| Keywords: |
DNA damage, biomonitoring, oesophageal cancer, barrett’s oesophagus, early cancer detection |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
Swansea University medical school, SURES scholarship |