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Title: Senescence and immortalisation in melanoma progression and multiple primary melanoma
Author: Kohli, Jaskaren Singh
ISNI:       0000 0004 6057 6749
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2016
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Multiple primary melanoma is defined as the gain of at least one additional independent melanoma and occurs in approximately 5% of melanoma patients. Germline mutations can be identified in genes in these patients, which are known to, or are predicted to result in an extension of melanocyte lifespan e.g. pl6, CDK4, and components of the telomere shelterin cap. We therefore hypothesised that 'normal' melanocytes from pl6 and CDK4 wild-type multiple primary melanoma patients have a statistically longer lifespan compared to those from single primary melanoma patients. Melanocytes from multiple primary melanoma patients did display a significantly extended culture lifespan, independently of donor age. Multiple primary melanoma is therefore commonly associated with a delay in normal melanocyte senescence. There is currently a shortage of diagnostic markers for melanoma and novel ones are needed for more accurate diagnosis and prognosis. TERT (the enzymatic component of telomerase) expression is the commonest route to telomere maintenance, required for melanoma immortality. TERT expression was tested via immunohistochemistry in a series of melanoma precursor and melanoma lesions, to analyse at which point in progression its expression is activated. The protein was found to be localised in either the nucleolus, the nucleoplasm (designated non-nucleolarTERT), or both. Only non-nucleolarTERT expression significantly increased with melanoma progression, suggesting this location is associated with immortality. As senescence likely needs to be bypassed for advanced melanoma development, microarrays were previously carried out comparing growing and senescent wild-type and pl6-null melanocyte lines to evaluate significantly up- or downregulated genes which could be used as future markers. In the present study, potential novel markers were authenticated using PCR and immunoblotting and validated genes were analysed via immunohistochemistry in a series of melanoma precursor and melanoma lesions. ETS1 was tested owing to recent findings that it can bind to and activate the mutant TERT promoter found commonly in melanomas. ETS1 was expressed at all stages from benign nevi onwards, perhaps owing to its link with the MAPK pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available