Review of genetics and epigenetics of Melanoma cancer

Melanoma is a type of skin cancer that develops in melanocytes, the cells that produce melanin, the pigment responsible for skin, hair, and eye color. Melanoma, particularly cutaneous malignant melanoma (CMM), is a complex disease characterized by both genetic and epigenetic alterations that contribute to its initiation, progression, and resistance to therapies. Understanding these mechanisms is crucial for developing effective diagnostic and therapeutic strategies. Methodology: With the keywords genetics, epigenetics, and melanoma, searches were performed in various databases such as NCBI and PubMed, and recent articles were studied, analyzed, and summarized. Results: Genetic Mutations of Melanoma There are some hotspots for melanoma in the human genome that are located on chromosomes ۱, ۶, ۷, and ۱۱. CDKN۲A: This tumor suppressor gene is frequently mutated or silenced in melanoma. Loss of p۱۶INK۴A, a protein produced by CDKN۲A, disrupts cell cycle regulation and promotes tumorigenesis. Germ-line mutations in CDKN۲A are associated with familial melanoma syndromes like FAMMM (Familial Atypical Multiple Mole Melanoma) which is an autosomal dominant disorder marked by the presence of numerous atypical moles (more than ۵۰) and a family history of melanoma. It is primarily associated with mutations in the CDKN۲A gene. Approximately ۴۰% of families with FAMMM syndrome carry this mutation. Individuals with this syndrome are at a heightened risk for developing multiple primary melanomas. They may also have an increased risk for other cancers, particularly pancreatic cancer, with estimates suggesting up to a ۱۷% increased risk. BRAF and NRAS: Oncogenic mutations in BRAF (particularly BRAF V۶۰۰E) and NRAS are common in melanoma cases, leading to constitutive activation of the MAPK signaling pathway, which drives cell proliferation and survival. Mutations in the BRAF gene, located on ۷q۳۴, are among melanoma's most common genetic alterations. Variants in genes such as MC۱R (associated with pigmentation), Mutations or deletions of PTEN, and amplification of the telomerase reverse transcriptase (TERT) gene also contribute to melanoma susceptibility. Epigenetic alterations in Melanoma DNA Methylation: Aberrant DNA methylation patterns are prevalent in melanoma, particularly hypermethylation of tumor suppressor gene promoters like PTEN and CDKN۲A. This silencing contributes to the loss of gene function and promotes tumor growth. Histone Modifications: Changes in histone acetylation and methylation also play significant roles in melanoma. For instance, the overexpression of EZH۲ (a histone methyltransferase) has been linked to aggressive tumor behavior and drug resistance. Non-Coding RNAs: MicroRNAs (miRNAs) such as miR-۱۲۴a and miR-۱۲۵b regulate gene expression post-transcriptionally and have been shown to influence melanoma cell proliferation and migration by targeting key oncogenic pathways. Epigenetic alterations can lead to transcriptional silencing of critical tumor suppressor genes, thereby enhancing the malignant phenotype of melanoma cells. These changes may also facilitate adaptation to environmental pressures such as therapy, contributing to treatment resistance. Genetic mutations and epigenetic modifications create a dynamic landscape that influences disease progression and patient outcomes. Conclusion: In summary, both genetic mutations and epigenetic modifications are integral to the pathogenesis of melanoma. Continued research into these areas is essential for advancing our understanding of the disease and improving therapeutic strategies.

کلیدواژه ها:

melanoma ، CDKN۲A ، BRAF ، PTEN ، EZH۲