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Title: Defining the role of microRNA-122 in the early detection of chemotherapy-induced hepatotoxicity in the neo-adjuvant treatment of advanced colorectal cancer
Author: McWhirter, Derek
ISNI:       0000 0004 5356 4643
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2014
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Colorectal cancer remains one of the most common cancers in the United Kingdom with around 40,000 new cases being diagnosed each year. Around 25% of patients will have liver metastases at the time of presentation, with up to 50% developing metastases at some point in their life. Advances in surgical technique and developments in chemotherapy have increased the number of patients with advanced disease for whom potentially curative treatment is possible. The use of chemotherapy in a neo-adjuvant setting has improved the outcome for patients with liver metastases who have initially irresectable or borderline disease. Chemotherapy-induced hepatotoxicity affects up to 78% of patients receiving standard chemotherapy for colorectal cancer and can lead to increased morbidity and mortality. Current gold standard serum-based biomarkers of drug-induced hepatotoxicity have their limitations and there remains a need for more sensitive and specific novel biomarkers to detect early hepatotoxicity. The use of serum-based microRNAs, in particular microRNA-122 (miR-122), a hepatocyte-specific molecule has been proposed as a possible biomarker for chemotherapy-2induced hepatotoxicity. The work described in this thesis assessed the characteristics of serum miR-122 in a healthy human population. It also assessed serum levels of miR-122 in different diseases including primary liver cancer. In order to assess the role of serum miR-122 in chemotherapy-induced hepatotoxicity, a pilot study was carried out in patients receiving chemotherapy for advanced colorectal cancer. In a healthy human population (n=129) serum levels of miR-122 were measured to investigate the degree of variation and define a normal reference range that could be used to assess changes found in patients with hepatic injury and disease. In addition to miR-122, two endogenous (U6snRNA/let27d) and one exogenous controls (c.lin24) were measured. Inter-individual variation was low for miR-122 (CV% 5.21) and also for all three controls (CV% <4%). There was no circadian variation in serum miR-122 (ANOVA p=0.1254). Analysis of intra-patient variation over three consecutive days was similarly low (p=0.66). In a human population with underlying chronic liver disease (n=90) and primary liver cancer (n=104), serum miR-122 was significantly raised in the both cohorts (p=<0.001) but no difference was seen between the chronic disease and cancer cohorts (p=0.338). Patients with an underlying inflammatory condition had significantly raised serum miR-122 (p=<0.001) compared to those with underlying cirrhotic or fibrotic change (p=0.372). ROC analysis supported this finding (AUC 0.79 vs 0.54). In a pilot study of serum miR-122 during neo-adjuvant chemotherapy for colorectal cancer liver metastases, 11 patients were recruited. Serial blood sampling during chemotherapy treatment revealed a non-significant rise in miR-122 (p=0.14). Clinically insignificant levels of liver toxicity were seen in the ten patients who completed the treatment and had surgery. In those with histology changes known to be associated with chemotherapy, there was a significant rise in serum ALT (p=0.0082 and 0.0085) while the miR-122 did not rise significantly (p=0.053). This work confirmed the low variation in serum miR-122 that is a requirement for a novel biomarker. Furthermore, it confirmed the detectable increase of serum miR-122 in patients with liver disease, particularly those with an inflammatory pathophysiology. Finally, in a human model of chemotherapy-related hepatotoxicity, the role of miR-122 remains unclear at present, but the non-significant changes in level related to clinically insignificant liver perturbation compared to the significant changes in ALT suggest that, although more work is required, it may be a valuable biomarker with potential in this field.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available