Molecular pathology as a tool to determine features of clinico-pathological progression and malignancy in melanocytic neoplasia

This thesis broadly comprises two investigations of melanocytic tumour progression.;1. The signalling ligand Wnt5a has been shown to promote motility and invasiveness in melanoma in vitro. To expand upon this data, expression of Wnt5a was examined in matched and unmatched tumour samples comprising different stages of melanoma progression. In order to place the alterations of Wnt5a in context, expression of p16INK4a and mutations of B-raf exon 15 were determined. The effect of Wnt5a expression on outcome was assessed.Wnt5a demonstrated a trend of increasing expression with progression (p = 0.013) however, expression in naevi was comparatively strong. When this was compared with p16ink4a expression and BRAF mutation, the changes supported a multi-step process of carcinogenesis. Survival analysis showed that Wnt5a is an independent marker of time to metastasis (p=0.041) and death (p=0.047).;2. B-raf and N-ras mutations are common in most melanocytic tumours, but are rare in Spitz naevi, where occasional H-ras mutations are found. The hypotheses were that Spitzoid tumours comprise a distinct subgroup of lesions that progress in the absence of B-raf and N-ras mutations, unlike most other melanocytic tumour types; but that progression from Spitz naevus to Spitzoid melanoma is unlikely because there is no subset of H-ras mutant Spitzoid melanomas. B-raf and N-ras mutations were found at lower frequency in Spitzoid melanomas (p=0.009) and in all Spitzoid tumour types (p=0.001) compared to non-Spitzoid melanomas, indicating that Spitz naevi and non-classical tumours are genetically distinct. H-ras mutations were not seen in malignant Spitzoid and non-Spitzoid melanomas indicating that H-ras mutant Spitzoid tumours do not progress to malignancy.;The findings of these investigations demonstrate the utility of molecular pathology in characterising neoplastic progression in archival melanocytic tumour tissue.