Critical molecular events in early skin carcinogenesis

Background: Cutaneous squamous cell carcinoma (SCC) is the second most common cancer to affect populations of European descent. It is potentially fatal and causes substantial morbidity. Up to 70% of SCC arise from clinically identifiable precancerous lesions, known as actinic keratoses (AK), permitting early diagnosis and intervention. Keratinocyte Intra-epidermal Neoplasia (KIN) are the histological representation of AK. Immunosuppressed organ transplant recipients have 60 – 200 fold higher rates of SCC that are characteristically multiple, aggressive, recurrent and have higher metastatic tendency. The molecular pathogenesis of SCC involves the accumulation of multiple genetic and epigenetic aberrations, but in spite of the magnitude of the problem, the cellular basis for SCC has received little scientific attention compared with other epithelial cancers. Methodology: Skin samples representing sequential keratinocyte carcinogenesis (from non sun-exposed, sun-exposed and AK/KIN skin) were collected from 53 individuals (31 immunosuppressed and 22 immunocompetent), 30 of whom underwent an additional biopsy after prospective treatment with one of three commercially available topical agents. Genome-wide single nucleotide polymorphism (SNP) profiling was performed on all samples and transcriptional profiling was performed on 7 series from each treatment group. Results: The mean number of SNP changes was 3.57 and 3.48 in NSE and SE skin, respectively, increasing to 6.93 in KIN. Several recurrent areas of loss or gain were identified in KIN, specifically deletion at 3p, 9p, 12q, 16q, 18q and X and amplification of 8q, 9p and 17p. Expression profiling identified 428 genes (false discovery rate 0.05) with altered expression in KIN skin compared to paired normal skin. Of these genes, 31% displayed concordant change with regions of copy number change. Several gene networks of interest were identified including F- and -actin, NFB, PPAR and TGF suggesting that they may be key pathways in KIN evolution. Several candidate genes in KIN skin continue to be dysregulated in SCC, some of which, such as ANG, S100A9, ACVR2A, FHL1 and SFN resolve after topical chemoprevention and others, WIF1, CCL27 and LEPR persist. Conclusions: This is the first systematic, in-depth, in vivo study of molecular events characterising KIN and provides a detailed profile of the critical events contributing to malignant progression in keratinocyte neoplasia and the molecular effects of widely used topical chemopreventive agents Together, these data provide clinically relevant insights into cutaneous squamous tumour biology and identify biomarkers with diagnostic, prognostic and therapeutic potential. AcknowledgementsEThOS - Electronic Theses Online ServiceGBUnited Kingdo