|dc.description.abstract||Non-melanoma skin (NMSC) cancer is the most common human malignancy. Cutaneous
squamous cell carcinoma (cSCC) and its precursor, actinic keratosis (AK) affect tens of
thousands of people each year in the UK. Merkel cell carcinoma is a rare, yet aggressive type of
NMSC recently linked with Merkel Cell Polyomavirus (MCPyV). In spite of the clinical burden of
NMSC, key molecular regulatory patterns remain largely unknown. The aims of this thesis were to
investigate genome-wide genetic, epigenetic and transcriptional changes in AK and cSCC, and
assess the prevalence of MCPyV and its effect on methylation in NMSC.
Copy-number analysis revealed that AK harbours significantly more genomic aberrations
compared to skin, the majority of which occurs on chromosomes 8 and 9. Transcriptional profiling
has found 292 and 308 genes as differentially expressed in AK compared to non-sunexposed and
sun-exposed skin, respectively, and gene-set enrichment analysis (GSEA) revealed dysregulation
of PPAR pathway in this lesion.
Expression profiling of cSCC and AK has revealed 346 differentially expressed genes, and GSEA
detected dysregulation in several canonical pathways including TGF-β and MAPK pathway.
Aberrant methylation in cSCC cell lines occurs in the promoters of many developmental genes. A
total of 1085 hyper- and 833 hypomethylated genes were detected in cSCCs, and GSEA revealed
dysregulation of critical signalling pathways (WNT, MAPK signalling pathways). Methylation
analysis of AK revealed a total of 4194 differentially methylated genes, and implicated FOXF2,
PITX2, RUNX1 and SMAD3 transcription factors in this lesions.
MiRNA profiling of cSCC and normal skin revealed significant dysregulation of 38 miRNAs
including several of viral origin.
MCPyV was shown to be common in NMSC, yet MCPyV nor human papillomavirus does not
affect cSCC methylation.
Taken together, this work provides novel insight into molecular regulation of cSCC oncogenesis,
and identifies potential epigenetic targets for functional evaluation in this malignancy.||en_US