Melanoma is a severe skin cancer arising from melanocytes, the cells producing skin pigment. Its development and progression are linked to specific genetic alterations, or mutations, in a cell’s DNA. These mutations influence how the cancer behaves and responds to various treatments.
The Role of Genetic Changes in Melanoma
Genetic mutations are alterations in a cell’s DNA sequence. In melanoma, these mutations often occur in melanocytes, frequently caused by ultraviolet (UV) radiation from sunlight or tanning beds. An estimated 90% of melanomas are directly attributed to UV radiation.
These mutations disrupt normal regulatory mechanisms controlling cell growth, division, and death. When genes responsible for these processes are altered, melanocytes can grow and divide uncontrollably, forming a tumor. Some mutations affect “tumor suppressor genes,” which protect cells from becoming cancerous, while others transform a cell by affecting “oncogenes” that promote uncontrolled growth.
Common Melanoma Mutations
Melanoma exhibits one of the highest rates of somatic mutations among all cancer types. The BRAF mutation is among the most frequently identified and clinically significant, found in about half of all melanomas. The most common variant, BRAF V600E, involves a specific change at residue 600, leading to hyper-activation of the MAPK signaling pathway. This activation promotes uncontrolled cell proliferation and survival.
Another significant group involves the NRAS gene, which also contributes to aberrant MAPK pathway activation. While less common than BRAF mutations, NRAS mutations are found in approximately 15-20% of melanomas. KIT mutations are observed, particularly in certain melanoma subtypes like acral or mucosal melanoma. These mutations lead to constitutive activation of the c-kit protein, which activates downstream pathways like MAPK and PI3K-AKT, inducing cell proliferation and enhanced survival.
Identifying Melanoma Mutations
Identifying specific mutations in melanoma patients guides clinical decisions. This process typically begins with a tumor tissue biopsy, which provides melanoma cells for genetic analysis.
Molecular testing methods, such as next-generation sequencing (NGS) and polymerase chain reaction (PCR), analyze the DNA. These technologies scan for known or new mutations within the tumor’s genetic material. The results provide detailed information for tailoring treatment strategies.
Mutation-Driven Therapies for Melanoma
The discovery of specific mutations, particularly in the BRAF gene, has changed melanoma treatment, enabling targeted therapies. These therapies block the activity of proteins produced by mutated genes. BRAF inhibitors directly target the mutated BRAF protein, while MEK inhibitors block a protein further down the same signaling pathway, disrupting uncontrolled cell growth.
Targeted drugs, such as vemurafenib (a BRAF inhibitor), can rapidly reduce tumor size in patients with BRAF mutations. Combining BRAF inhibitors with MEK inhibitors, like dabrafenib and trametinib, has shown improved outcomes by more effectively blocking the signaling pathway and reducing resistance. The presence of specific mutations allows for a personalized medicine approach, where treatment is tailored to the individual’s genetic profile of their tumor. While immunotherapy, which boosts the body’s immune response against cancer, is another important treatment, the presence of certain mutations can sometimes influence how these therapies are used or when they might be considered alongside targeted treatments.