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Mutational and Functional Analysis of the Melanoma Genome

Final Report Summary - MELGEN (Mutational and Functional Analysis of the Melanoma Genome)

Melanomas, the deadliest form of human skin cancer, frequently harbour mutations in multiple genes. Blocking the activity of key mutant genes has led to meaningful clinical benefits in a subset of patients. The success of this approach (known as targeted therapy) is based on the premise that curbing the activity of critical genes, which “drive” tumour survival, would not be tolerated by the tumour. Therefore identifying these “driver” genes is essential to develop new therapies that can benefit thousands of patients for whom there are limited treatment options. Using various sequencing technologies, during this project, we as well as others have collected a large amount of data, identified the melanoma genetic landscape and identified the major mutant genes in human melanomas. This has resulted in the development of new drugs targeting the proteins that are most frequently altered in melanoma which have recently resulted in major life-prolonging breakthroughs (3). However, not all patients’ tumours are amenable to these treatments. Moreover, in patients that do respond to treatment, the heterogeneous nature of melanoma tumours leads to the rapid emergence of resistance. In this project we further analysed the genetic basis of melanoma, to identify novel drug targets for patients who do not respond to existing treatments. During these studies we identified a novel melanoma protein called RASA2 which is lost in 35% of melanoma patients. Importantly, when this protein is lost, the survival of melanoma patients is reduced significantly. We have therefore identified a novel melanoma prognostic marker. In parallel, using our melanoma genetic database, we have identified several additional melanoma genes. The functional effects of the mutated genes on melanoma growth and patient survival has validated the fact that these have a role to play in the disease. To this end, we have used models that closely simulate the environment in which melanomas develop. These models, known as isogenic patient derived cells, represent the original genetic environment in which the mutations arose. We are introducing mutant genes or silencing the expression of mutant genes in melanoma cells to study their role driving melanoma. In parallel, we have developed a novel unbiased approach to search for protein interactors, which make it possible to identify the interaction partners of endogenous human proteins in human cells. Importantly, establishing the protein interaction network of melanoma mutated proteins will provide a comprehensive understanding of their role in the disease. We expect that our studies will uncover how melanoma genes control melanoma and reveal options for their molecular targeting, which will in turn generate insights to aid the treatment of melanoma patients.