Melanoma progressses through 5 phenotypically distinct stages: benign nevus, dysplastic nevus, radial-growth phase, vertical-growth phase, culminating in metastatic melanoma. Environmental and genetic factors play a role in the disease progression. Oncogenic mutations in B-Raf and N-Ras activate the Raf-MEK-ERK pathway while mutations in N-Ras and PTEN activate the PI3K-AKT pathway leading to uncontrolled proliferation and cell survival. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression.
Melanoma development is also associated with genetic alterations to genes in tumor supressor pathways. Genes that are mutated include p16INK4a and CDK4 from the retiblastoma pathway and p14/ARF and p53 from the p53 pathway.
Microphthalmia-associated transcription factor (MITF) acts as a master regulator of melanocyte development, function and survival by modulating differentiation and cell-cycle progression genes. MITF is an amplified oncogene in a fraction of human melanomas.