The Genomic Atlas of Dermatological Tumours (DERMATLAS)

There is a misconception that skin cancers, Europe's most common type of tumour, are treatable with surgery and are thus not a research priority. The reality is that while many patients can be adequately managed with surgical intervention, surgery is often disfiguring and can be associated with significant morbidity. Notably, many skin tumour types such as cutaneous angiosarcoma, Merkel cell carcinoma and some sarcomatoid/spindle cell carcinomas are associated with an extremely poor prognosis.

Importantly, in the clinic the classification of skin tumour types can be extremely challenging, particularly determining benign from malignant lesions with the exact diagnosis having profound implications for patient outcome and management. Unlike more common cancers, the genomes of most skin malignancies have not been studied in detail and treatment options in advanced disease are limited. In terms of the etiology of skin cancers, another misnomer is that most skin cancers are UV-associated. While this is certainly the case for some types of melanoma, BCCs and squamous cell carcinoma, the cause of most other types is unknown. Some tumours such as Merkel cell carcinoma are associated with viruses (Merkel cell polyomavirus) while HPV has been suggested to play a role in other entities but the role of viruses or other exposures has been poorly explored. In this project we plan to use genetic analysis to identify how and why a wide range of skin tumours develop, with the possible implications for this work being enhanced patient management, better diagnosis and an improved understanding of the basic biology of skin.

Our overarching hypotheses for the studies proposed in this grant are that: 1). Most skin tumour subtypes can be defined by a discrete set of drivers, some of which can be targeted therapeutically; 2). Some skin tumours are caused by germline predisposing alleles, chemical exposures or viruses and these can be revealed by DNA/RNA sequencing and analysis. Collectively these studies can help define new screening and public health approaches. Specifically we will use state-of-the-art DNA sequencing technology to identify somatic and germline variants in 70 skin tumour entities defined by the WHO so that we can generate an atlas of dermatological tumours. We have a proven track record in this area and this grant represents a scaling up of our already successful programme of work.

Academic impact
Our primary output, as with all academics, will be research papers. Our results will also be communicated to basic science/clinical colleagues via conferences and our network of collaborators. These interactions will enable the data to be used as part of candidate gene prioritisation studies and for drug development. Interest and engagement with the project will also be achieved via our lab website and the Sanger Institute website and through blogs and tweets.

Economic and societal impacts
One of the groups of people we hope will benefit from our work is patients. This will initially be through enhanced diagnostics, which impact patient care and since we hope to identify exposures that promote skin tumour development by exploring mutational signatures, and by searching for viruses, it is possible the general public will also benefit through enhanced public health/education.

Public engagement activities will be performed to allow dissemination of the findings of our study to the wider public. The Wellcome Sanger Institute and the University of Cambridge both have well established public engagement teams to assist with this process. Further, our work will be communicated via science fairs and workshops which are held with the general public and also at schools - Dr. Adams leads the Cambridge Cancer Institute Cell and Molecular Biology Programme which has a very active outreach programme (https://crukcambridgecentre.org.uk/research/programmes/cellular-and-molecular-biology). The aim of these activities is to communicate the basic concepts of cancer genetics and to place in context the studies that will be performed as part of this grant. As publications are submitted and accepted we will write press releases to ensure media coverage of our work - these documents will use lay language to enhance public engagement and understanding.

Dr. Adams works with patient advocates and speaks at the local Cambridge cancer support group. This forum represents another way we will enhance public awareness of our work.

We will work with the MRC/Sanger translation offices to protect any intellectual property that may arise from these studies funded by this grant. Through links established with Open Targets funded projects (a pioneering public-private partnership between Biogen, Celgene, EMBL-EBI, GlaxoSmithKline, Takeda, and the Wellcome Sanger Institute) and other collaborations, the Adams lab has a network of contacts to disseminate the finding of our studies to the biotech community. These interactions will allow potential drug targets to be identified and if suitable to enter clinical development. We also work with BMS, AZ and the Milner institute each of whom represent avenues for translation.