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Title: Recombinant tumor-associated antigen production and autoantibody detection in hepatocellular carcinoma
Author: Middleton, Catrin Heledd
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
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Hepatocellular carcinoma (HCC) is the sixth most common cancer and third most common cause of cancer-related death worldwide. Inadequate screening tests largely account for presentation of advanced tumours, poor prognosis and high mortality rates. Major risk factors for the development of HCC include Hepatitis B and C Virus infections and alcoholism, which lead to irreversible liver cirrhosis. Early detection of HCC amongst high-risk groups is paramount in improving prognosis, through enabling curative treatment options to be administered prior to manifestation of advanced and metastatic disease. An elicited humoral immune response, in the form of IgG autoantibodies raised to tumour-associated antigens, has been evidenced in the sera of cancer patients. Autoantibody measurements, using a minimally invasive blood test, could serve as an aid to early diagnosis by providing a window on early carcinogenesis months to years before the tumour bulk becomes otherwise clinically detectable. Autoantibody detection has previously been described in the HCC setting. Small numbers of antigens and use of sub-optimal control sera render published studies open to scrutiny. This thesis documents the research carried out in order to characterise the previously documented autoantibody response in the sera of patients with HCC and underlying liver disease. Tumour-associated antigens were produced using high-throughput recombinant technology and screened against sera from patients with HCC, liver disease and matched healthy controls. Varying autoantibody specificities and sensitivities were observed to the individual tumour-associated antigens investigated. A panel of 21 antigens achieved a specificity of 92% and sensitivity of 45% for the detection of HCC (by testing 96 cancers and 96 matched healthy controls). This same panel identified 21 % of 169 high-risk controls as having elevated autoantibody levels. This highlights the need for further investigation in order to determine whether such specificity (79%) would be deemed acceptable in a clinical setting for the application of an autoantibody test to aid in earlier cancer diagnosis. A reproducible panel of II antigens achieved a specificity of 91 % and sensitivity of 41 % for the detection of HCC, suggesting the potential held by optimised antigen production and careful panel selection. Changing autoantibody profiles in the sera of patients with stable cirrhosis and in the pre- and post-diagnostic sera of patients with HCC suggests a potential role for autoantibodies and their detection in the surveillance, diagnosis and prediction of recurrence in the HCC setting. Results are comparable to current gold standards in HCC (Ultrasonography) and to similar tests in other cancers (Early-CDT®-Lung). This simple blood test has the potential to offer a competitive advantage over currently available tools for the early identification of HCC amongst patients routinely monitored for the progression of their underlying liver disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available