Development and validation of an autoantibody-based blood test for hepatocellular carcinoma

Welberry, Christopher J. (2019) Development and validation of an autoantibody-based blood test for hepatocellular carcinoma. PhD thesis, University of Nottingham.

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Abstract

Hepatocellular carcinoma is the 4th leading cause number of cancer related deaths worldwide. Detection of Hepatocellular carcinoma (HCC) at an early stage is crucial for a positive prognostic outcome, however early detection is hindered by the paucity of early symptoms and interference of underlying liver disease with imaging modalities. Assessment of Alpha-fetoprotein (AFP) as a blood-based screening/diagnostic tool for HCC is still under scrutiny as many HCC tumours do not produce elevated levels and levels can be elevated in other liver disease patients.

Autoantibodies to tumour associated antigens have been shown to be present in the blood of patients with numerous solid malignancies including HCC and, in some cases, have been reported to be detectable before clinical diagnosis. This thesis will look to expand on previously published work which demonstrates the presence and utility of such autoantibodies to detect HCC from high-risk liver disease patients and how this could fit into the clinical pathway for such patients.

As such, this thesis documents the process of characterising autoantibody responses in such patients to previously described tumour-associated antigens along with the characterisation of novel autoantigens. Autoantibody responses were measured using ELISA against recombinant antigens produced in E. coli. The final autoantibody panel was formed through multiple studies including training and validation of the final panel in independent patient cohorts.

A final panel of 11 autoantibodies was selected from training assays and validated in a separate cohort with no significant difference in accuracy. The panel of 11 could detect HCC with a sensitivity of 42% and a specificity of 88.2% in the training and validation cohorts combined. AFP measurement was significantly additive to the 11-autoantibody panel resulting in sensitivity and specificity of 56.3% and 87.8% respectively. Importantly the combined panel sensitivity for BCLC stage A HCCs, was greater than 55%, with current tests often showing stage A sensitivities of less than 50%.

This thesis shows autoantibodies can distinguish HCC from patients with chronic liver and most importantly at stages with a favourable prognosis. Autoantibodies could also be combined with AFP antigen measurements to improve on either test alone. This thesis also brings this autoantibody panel closer to a commercial test by assessing performance in independent training and validation cohorts.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Chapman, Caroline J.
Irving, William L.
Keywords: Liver cancer; Diagnosis; Autoantibodies; AFP antigen measurements; Blood tests
Subjects: W Medicine and related subjects (NLM Classification) > WI Digestive system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 56243
Depositing User: Welberry, Christopher
Date Deposited: 19 Jul 2019 04:40
Last Modified: 07 May 2020 11:46
URI: http://eprints.nottingham.ac.uk/id/eprint/56243

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