How does RAS contribute to cutaneous squamous cell carcinoma?


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Angela McHugh1, Mark Saville1, Catherine Harwood2, Karin Purdie2, Alan Evans3, Aidan Rose1, Colin Fleming4, Irene Leigh1, Andrew South1, Charlotte Proby1
1Division of Cancer Research, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK, 2Centre for Cutaneous Research, Barts and the London Queen Mary University of London, London, UK, 3Department of Pathology, Ninewells Hospital & Medical School, Dundee, UK, 4Department of Dermatology, Ninewells Hospital, Dundee, UK

Background

Cutaneous squamous cell carcinoma (cSCC), the second most common skin cancer, is a major problem in our ageing population. In Scotland, there has been a 55% increase in cSCC incidence in the decade 2000-2010, with a 50% increase in workload for UK dermatologists predicted by 2030. TP53 and NOTCH genes are identified as important tumour suppressors, but critical oncogenes for cSCC are yet to be defined. Activating mutation in HRAS is the initiating event in the mouse chemical carcinogenesis model but, in mouse and human xenograft models of cSCC, oncogenic ras alone is insufficient for invasive malignancy and additional genetic manipulation is necessary. The role of oncogenic ras in human cSCC is even less clear, but has clinical relevance given the therapeutic potential for targeting MAPK and PI3K signaling with inhibitors.

Method

Whole exome sequencing of 20 cSCC was undertaken using Agilent exome capture arrays sequenced on the Illumina Hi-Seq platform, with validation in 82 cSCC (DNA amplified on the Fluidigm Access Array and sequenced using the Roche 454 Junior System).

Results

Activating mutations of RAS were present in 11% of 102 cSCC. The frequency was 3-fold higher (35%) in an additional 20 squamous neoplasms arising in the context of vemurafenib treatment for BRAF-mutant melanoma, suggesting RAS mutation may be a frequent event in human keratinocytes, but often will not progress to invasive SCC due to oncogene-induced senescence. NOTCH1 was the only known cancer driver, other than RAS, significantly mutated in vemurafenib-tumours (60%) and activating RAS mutation co-segregated with NOTCH1 mutation in the validation cohort of 82 cSCC.

Conclusion

These data suggest that suppression of NOTCH1 is important for ras-driven clonal proliferation. Kinase inhibitors alone and in combination are being used to dissect the ras pathway-dependency of a panel of cSCC cell lines.