Malignant melanoma, one of the three major skin cancers, is associated with the worst outcome due to its propensity to metastasize and resistance to therapy of advanced disease. About 20 percent of melanomas progress to local and distant metastases.
Additionally, development of secondary primary melanomas contributes to enhanced personal burden. At present the treatment of metastatic melanoma due to onset of resistance remains an exercise in disease management. Therefore, identification of genetic markers of advanced disease that could help in identification of patients with primary melanoma at particularly high risk of developing metastases or secondary melanomas remains a crucial task and the aim of the present project.
To fulfil the aims of the project, tumors from primary melanoma patients with and without metastases were screened for genetic alterations by exome sequencing and genome-wide analysis of retroelement insertions.
In addition epigenetic alterations in primary melanomas were also investigated. Exome sequencing has been also been carried out on patients with multiple melanomas. The data from those analyses have been and are currently being validated in our unique collection of tumors from melanoma patients.
The markers identified so far are being tested through functional studies for possible use in clinical practice. Besides detecting numerous novel mutations and identifying the functional pathways involved in melanoma, our data showed that the TERT promoter mutations defined patients with poor survival. In addition, we identified a combination of specific mutations that defines patients at risk for developing advanced disease and poor survival. Moreover, we also observed that the overall mutational burden has an effect on progression and survival in melanoma patients.