[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [General pathology](https://durgical.com/en/general-pathology/) › [Skin](https://durgical.com/en/general-pathology/areas/skin/) › Melanoma: pathogenesis # Melanoma: pathogenesis - Mechanism Melanoma is the most dangerous skin cancer. Sun damage causes gene changes in pigment cells, which first spread sideways and then grow deep. Updated Nov 12, 2026 ## Key points - Risk factors: intermittent intense UV exposure and sunburns, fair skin, many or dysplastic nevi, family history, immunosuppression, xeroderma pigmentosum. - Drivers: BRAF V600E (about half of cutaneous melanomas), NRAS, NF1 loss; KIT in acral and mucosal melanoma. - Familial melanoma: germline CDKN2A (p16 and p14ARF), also CDK4; risk of pancreatic cancer in CDKN2A families. - TERT promoter mutations are among the commonest changes. - Radial growth phase: spreads within the epidermis, cannot metastasise; vertical growth phase: grows into dermis as a nodule, gains metastatic potential. - High neoantigen load makes melanoma responsive to checkpoint inhibitors. ## What it is Melanoma arises from melanocytes, mostly in skin, after ultraviolet light induces many mutations. Its genome carries some of the highest mutation loads of any cancer, which is also why immunotherapy works. Driver mutations activate MAP kinase signalling (BRAF, NRAS, NF1 loss, KIT in acral and mucosal types), and loss of cell-cycle control (CDKN2A) and telomerase activation (TERT promoter) let it progress. Its growth phases explain why thickness predicts outcome. ## Step by step - UV light (mainly UVB) causes pyrimidine dimers and C-to-T mutations in melanocyte DNA. - An activating BRAF or NRAS mutation drives proliferation (often first as a nevus). - Loss of CDKN2A releases CDK4/6 and lets cells escape senescence. - TERT activation and further mutations give immortality; cells spread laterally (radial growth). - A subclone invades the dermis as a nodule (vertical growth), evades immunity and metastasises. ## Melanoma drivers by site | Setting | Common drivers | Sun link | | --- | --- | --- | | [Intermittently sun-exposed skin (trunk)](https://durgical.com/en/conditions/melanoma/) | BRAF V600E | Intermittent intense UV | | [Chronically sun-damaged skin (face of older people)](https://durgical.com/en/conditions/melanoma/) | NRAS, NF1, KIT | Cumulative UV | | [Acral (palms, soles, nails)](https://durgical.com/en/conditions/melanoma/) | KIT, copy-number changes | Little or none | | [Mucosal](https://durgical.com/en/conditions/melanoma/) | KIT, NRAS | None | | Uveal | GNAQ, GNA11, BAP1 | None | ## Clinical notes - BRAF V600E tumours respond to BRAF plus MEK inhibitors; checkpoint inhibitors work across subtypes. - In Latin America and in people with darker skin, acral lentiginous melanoma is a relatively larger share and is often diagnosed late. ## Memory aid Melanoma first spreads like spilled ink across the paper (radial), then soaks through it (vertical); only the soaking ink reaches the blood. ## Test yourself Think of the answer, then tap the question to see it. ## Which gene is mutated in familial melanoma? CDKN2A, encoding the p16 CDK inhibitor (and p14ARF); CDK4 less often. ## Why can a radial growth phase melanoma not metastasise? It is confined to the epidermis (and superficial papillary dermis) with no access to vessels and lacks the clones that invade. ## Which driver is typical of acral and mucosal melanoma? KIT mutations (with fewer BRAF mutations than on sun-exposed skin). [Add to my cards (3)](https://durgical.app/estudiar/?add=/en/general-pathology/melanoma-pathogenesis/) [More Pathology questions →](https://durgical.com/en/practice/?f=pathology) ## Elsewhere in DurgiPedia - [Radiation and cancer: ultraviolet and ionizing](https://durgical.com/en/general-pathology/radiation-and-cancer-ultraviolet-and-ionizing/) - [Oncogenes: RAS, MYC, HER2, BCR-ABL and the table to know](https://durgical.com/en/general-pathology/oncogenes-ras-myc-her2-bcr-abl-and-the-table-to-know/) - [Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis](https://durgical.com/en/general-pathology/tumour-suppressor-genes-rb-tp53-apc-brca-and-the-two-hit-hypothesis/) - [How tumours evade the immune system](https://durgical.com/en/general-pathology/how-tumours-evade-the-immune-system/) ## Connections ## Related 5 - [Freckles, lentigines and melanocytic nevi](https://durgical.com/en/general-pathology/freckles-lentigines-and-melanocytic-nevi/) - [Melanoma: subtypes, Breslow and markers](https://durgical.com/en/general-pathology/melanoma-subtypes-breslow-and-markers/) - [Radiation and cancer: ultraviolet and ionizing](https://durgical.com/en/general-pathology/radiation-and-cancer-ultraviolet-and-ionizing/) - [How tumours evade the immune system](https://durgical.com/en/general-pathology/how-tumours-evade-the-immune-system/) - [The cell cycle in cancer: cyclins, CDKs and checkpoints](https://durgical.com/en/general-pathology/the-cell-cycle-in-cancer-cyclins-cdks-and-checkpoints/) ## Related conditions 4 - [Melanoma](https://durgical.com/en/conditions/melanoma/) - [Melanocytic nevi and dysplastic nevus](https://durgical.com/en/conditions/melanocytic-nevi-and-dysplastic-nevus/) - [Xeroderma pigmentosum](https://durgical.com/en/conditions/xeroderma-pigmentosum/) - [Pancreatic cancer](https://durgical.com/en/conditions/pancreatic-cancer/) [← All of general pathology](https://durgical.com/en/general-pathology/) Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given. Sources: [Melanoma](https://medlineplus.gov/genetics/condition/melanoma/) (MedlinePlus, US National Library of Medicine, 2025); [Genetics of Skin Cancer (PDQ®)–Health Professional Version](https://www.cancer.gov/types/skin/hp/skin-genetics-pdq) (National Cancer Institute, 2025). ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/general-pathology/melanoma-pathogenesis/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/general-pathology/melanoma-pathogenesis/