The Genetic Basis of Dormancy and Awakening in Cutaneous Metastatic Melanoma

SIMPLE SUMMARY: Advanced malignant melanoma still has a poor prognosis. Mortality is closely associated with tumor recurrence, which, as with other types of cancer, can occur after long periods of clinical remission. Clinical latency is related to the ability of residual tumor cells to persist in a dormant state, without proliferation. In this paper, we review the genetic profile of melanoma cells from their appearance, through the dormant state to their reactivation leading to metastasis. A complete genetic profile will enable the genes responsible for metastasis appearance to be identified and thus contribute to creating new therapeutical targets that keep cells in a dormant state and prevent melanoma tumor cells from spreading. ABSTRACT: Immune dysregulation, in combination with genetic and epigenetic alterations, induces an excessive proliferation of uncontrolled melanoma cells followed by dissemination of the tumor cells to distant sites, invading organs and creating metastasis. Although immunotherapy, checkpoint inhibitors and molecular targeted therapies have been developed as treatment options for advanced melanoma, there are specific mechanisms by which cancer cells can escape treatment. One of the main factors associated with reduced response to therapy is the ability of residual tumor cells to persist in a dormant state, without proliferation. This comprehensive review aimed at understanding the genetic basis of dormancy/awakening phenomenon in metastatic melanoma will help identify the possible therapeutical strategies that might eliminate melanoma circulating tumor cells (CTCs) or keep them in the dormant state forever, thereby repressing tumor relapse and metastatic spread.