Ross, David Anthony; (1996) Clinical significance of the p53 and c-myc proteins in melanoma. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Malignant melanoma continues to present significant epidemiological, prognostic and therapeutic problems that are unlikely to be resolved without greater understanding of its biology. Considerable interest centres on the molecular genetics of cancer, and in particular, the role of oncogenes known to be important in control of cellular growth and proliferation. In this thesis, dual parameter flow cytometry was used to study expression of the protein products of the tumour suppressor gene, p53, and the nuclear oncogene, c-myc, in patients with cutaneous melanoma. In addition, flow cytometry was also used to measure the proliferation kinetics of these tumours in vivo using bromodeoxyuridine. These parameters were related to each other and the clinico-pathological features of each tumour. p53 and c-myc protein expression were also investigated in benign and dysplastic naevi. Expression of both oncoproteins was prevalent in melanoma. Eighty percent of ethanol-fixed melanomas were p53-immunopositive, but expression showed limited association with clinical parameters, other than ulceration and patient age. c-myc was detected in 79% of primary tumours and 89% of metastases and increased with thickness of the primary tumour (p = 0.008). Using univariate analysis, the level of c-myc expression was prognostically significant in patients with thick primary melanomas (>3mm) (p = 0.02) and stage 2 (P = 0.04) disease. Prevalence of both p53 and c-myc positivity in 94 paraffin-embedded melanomas were similar to those observed in ethanol-fixed tumours. Using multivariate analysis, the level of c-myc expression was associated with patient survival (p = 0.02) in patients with thick melanomas. The median tumour potential doubling time (Tpot) was shorter in thick primary melanomas (p = 0.03) and inversely associated with the level of c-myc oncoprotein expression (p = 0.02). Proliferation kinetics did not vary between primary and metastatic melanomas. BMN were immunonegative for p53, whilst 53% of DN were P53-positive. c-myc expression was prevalent in both types of naevi, but at significantly lower levels than observed in melanomas (p = 0.04). In conclusion, the findings of this study suggest stabilisation of the p53 protein may represent an epiphenomenon and be of limited clinical significance. Proliferation kinetics may explain tumour behaviour in a further subgroup of patients. This study suggests c-myc oncoprotein has a more central role in melanoma biology than previously considered and may be of prognostic significance. Further investigation of this oncogene may provide greater understanding of melanoma behaviour and an objective platform upon which to design future therapy.

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