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Using DNA damage in circulating blood cells as a biomarker for oesophageal adenocarcinoma risk / Kathryn Munn

Swansea University Author: Kathryn Munn

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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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Published: Swansea, Wales, UK 2025
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Jenkins, Gareth ; Doak, Shareen
URI: https://cronfa.swan.ac.uk/Record/cronfa69525
first_indexed 2025-05-16T09:45:26Z
last_indexed 2025-05-17T07:24:45Z
id cronfa69525
recordtype RisThesis
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spelling 2025-05-16T10:56:59.0330634 v2 69525 2025-05-16 Using DNA damage in circulating blood cells as a biomarker for oesophageal adenocarcinoma risk 1c7f25073bd2fc065aa2d9bb54062879 0009-0009-0960-6328 Kathryn Munn Kathryn Munn true false 2025-05-16 MEDS 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. E-Thesis Swansea, Wales, UK DNA damage, biomonitoring, oesophageal cancer, barrett’s oesophagus, early cancer detection 14 5 2025 2025-05-14 10.23889/SUthesis.69525 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Jenkins, Gareth ; Doak, Shareen Doctoral Ph.D Swansea University medical school, SURES scholarship Swansea University medical school, SURES scholarship 2025-05-16T10:56:59.0330634 2025-05-16T10:42:18.2535517 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Kathryn Munn 0009-0009-0960-6328 1 69525__34293__f2954e0505194a61b165f3cd154ecdaa.pdf Munn_Kathryn_O_PhD_Thesis_Final_Cronfa.pdf 2025-05-16T10:53:54.4751590 Output 10684046 application/pdf E-Thesis – open access true Copyright: The Author, Kathryn Olivia Munn, 2025. true eng
title Using DNA damage in circulating blood cells as a biomarker for oesophageal adenocarcinoma risk
spellingShingle Using DNA damage in circulating blood cells as a biomarker for oesophageal adenocarcinoma risk
Kathryn Munn
title_short Using DNA damage in circulating blood cells as a biomarker for oesophageal adenocarcinoma risk
title_full Using DNA damage in circulating blood cells as a biomarker for oesophageal adenocarcinoma risk
title_fullStr Using DNA damage in circulating blood cells as a biomarker for oesophageal adenocarcinoma risk
title_full_unstemmed Using DNA damage in circulating blood cells as a biomarker for oesophageal adenocarcinoma risk
title_sort Using DNA damage in circulating blood cells as a biomarker for oesophageal adenocarcinoma risk
author_id_str_mv 1c7f25073bd2fc065aa2d9bb54062879
author_id_fullname_str_mv 1c7f25073bd2fc065aa2d9bb54062879_***_Kathryn Munn
author Kathryn Munn
author2 Kathryn Munn
format E-Thesis
publishDate 2025
institution Swansea University
doi_str_mv 10.23889/SUthesis.69525
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description 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.
published_date 2025-05-14T05:28:25Z
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