Computational Analysis of Transcription and Alternative Splicing Events in Squamous Cell Cancer.

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Squamous cell carcinomas (SCCs) are a very common type of human cancer which affect surface in the body, such as the skin, cervix (neck of the womb) and the lining of the mouth and throat. There has been little progress towards finding new and successful treatments for these important cancers, although recent studies have drugs which target sets of genes that drive the SCC to occur do help. I will study in detail how SCCs are affected by a process called "alternative RNA splicing".The DNA in our cells contains a code which is 'read' to make messenger molecules called RNA. The useful bit of the code which is turned into RNA are the genes, and within each gene, the 'words' of the message are alternated with areas of irrelevant code. To get a meaningful message, the useful words need to be 'spliced' together and the irrelevant bits spliced out. That process is called RNA splicing. In some genes, more than one meaningful message can be made from one set of DNA words by 'alternative RNA splicing'. That can be part of how cells function normally, but if it goes wrong it can damage the message produced, potentially making a cell function less well or to grow out of control (as in cancer). Controlling this splicing involves a complex mix of proteins, including 'splicing factors' and 'RNA binding proteins'. RNA splicing is changed in cancer cells but for individual cancer types, we do not understand the full range of the changes, nor which of them would make the best targets for new treatments or tests.I will identify splicing changes that are common to SCCs, and also those that are specific to a particular site and/or cause. I will look at samples from patients' SCCs that come from two different sites in the body - the skin and the cervix. These have different causes, particularly sunlight in the skin and infection with a virus (the human papillomavirus) in the cervix.I will use powerful new technologies to read the sequence of all the RNA molecules in the samples. I will join a unique collaboration between the European Bioinformatics Institute (EBI) and Cambridge University. I will be based with Dr Anton Enright at the EBI, a world-renowned centre for biological computing near Cambridge, and will undertake the experimental and clinical aspects of the project in the laboratory of Professor Nicholas Coleman at Cambridge University Department of Pathology. Together, these highly complementary environments will provide me with the ideal platform to complete this work successfully and to develop my career as an academic doctor.Using databases of gene studies from large projects in America, I will be able to see if the changes I've found make a difference to how long patients with cancer survive and respond to drugs. These databases have information for a wide range of cancers, including various SCCs, but none for normal, healthy tissue - which is why this project is needed.All the results I generate will be made available openly using a secure database that can be accessed through the internet, and any scientific papers that I publish based on this work will be freely available to anyone to read.My project will greatly improve our understanding of how RNA splicing works in SCC cancer cells and will identify differences between SCCs that have particular causes and/or occur at specific sites in the body. The work will open up new opportunities for diagnosing and/or treating a variety of common SCCs.