A89
Identification of therapeutic and prognostic biomarkers in keratinocyte carcinogenesis
Abha Gulati, Catherine Harwood, David Kelsell, Charlotte Proby
Institute of Cell and Molecular Science, London, UK
Background
Keratinocyte skin cancers (KSC) comprising BCC and SCC are the commonest malignancies in humans with over 100,000 cases diagnosed in the UK each year. Up to 80% primary SCC arise in clinically apparent areas of precancerous keratinocyte intraepithelial neoplasia (KIN). Early identification and treatment of KIN is likely to have a significant impact on stemming the increasing burden of KSC.
Method
Integrated Genome-wide SNP and mRNA expression microarrays on skin samples representing sequential stages of evolution of KIN including normal non-sun exposed (NSE), normal sun exposed (SE) and KIN skin, such as dorsum of hands or forehead, from 30 high-risk organ transplant recipients and 20 immunocompetent subjects with previous SCC. 30 of these subjects also received treatment of KIN with three widely used topical agents: 5-flourouracil; imiquimod and COX II inhibitor followed by a further post-treatment biopsy.
Results
Initial analysis of SNP data has revealed several recurrent areas of loss or gain, specifically loss at chromosome 1p, 3p, 4p, 9p and 19p and a gain at chromosome 8q containing several potential candidate genes, such as EPS15 and GATAd2A, a transcriptional repressor involved in methylation.
Early results of mRNA array analysis have provided lists of genes differentially regulated through the different stages of KIN evolution and indicated involvement of a number of important gene ontology pathways, such as Keratin filament cytoskeleton remodelling and IL10 signalling.
Conclusion
In summary, this research will provide a comprehensive, integrated profile of key genetic and expression changes in early skin carcinogenesis, permitting identification of critical events in the evolution of KIN, development of diagnostic and prognostic biomarkers and identification of novel therapeutic targets directed at KIN, Ultimately such information may be used to refine therapeutic strategies in attempts to stem the mounting incidence and burden of SCC.
