Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.791353
Title: Biomarkers of mismatch repair deficiency in colorectal cancer and cancer predisposition syndromes
Author: Gallon, Richard John
ISNI:       0000 0004 8501 9746
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2019
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Abstract:
Colorectal cancer (CRC) is the third most common cancer in Western societies and approximately 15% are mismatch repair deficient (MMRd). MMRd CRCs have a distinct prognosis, respond to immunotherapy, and occur at a high rate in patients with Lynch syndrome or constitutional mismatch repair deficiency (CMMRD). Detection of MMR deficiency, therefore, guides treatment and identification of associated cancerpredisposition syndromes. However, there is a need for novel biomarkers to detect MMRd CRC, and innovative assays to improve Lynch syndrome and CMMRD diagnosis. I assessed autoantibodies generated against MMRd CRCs as a liquid-biopsy biomarker for cancer detection, by analysing the sera of 464 Lynch syndrome gene carriers using a recently published, multiplex method. Although autoantibodies correlated with a history of CRC, a lack of signal from patients who developed CRC shortly after sampling suggests the method has poor sensitivity. Microsatellite instability (MSI) is an established biomarker of MMR deficiency. I used single molecule molecular inversion probes to develop a sequencing-based MSI assay with an automated results analysis, suitable as a companion diagnostic for immunotherapy, and for streamlined Lynch syndrome screening. The assay achieved 100% accuracy in 197 CRCs, and was robust to sample variables, including quantity, quality, and tumour cell content. Subsequently, I adapted the MSI assay to detect low-level MSI in non-neoplastic tissues of CMMRD patients. The assay separated all 32 CMMRD patients from 94 controls. For both CRC and CMMRD diagnostics, the MSI assay is cheaper and faster than current methods, and is scalable to large cohorts. These results suggest that the humoral immune response to MMRd CRCs cannot readily be used as a biomarker to detect disease, and that alternatives should be sought. However, the MSI assay could be deployed into clinical practice to meet the high demand for MMR deficiency testing of CRCs and to improve CMMRD diagnostics.
Supervisor: Not available Sponsor: Barbour Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.791353  DOI: Not available
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