Moles are very common, especially in people with fair skin. Moles are overgrowths of skin cells called melanocytes, but the genetic factors involved in their development are not well understood. Although moles, like tumors, are an overgrowth of cells, moles are almost always noncancerous (benign). Perhaps because most moles are benign, scientists have not studied them extensively, and not much is known about their genetics. Similar numbers of moles seem to occur on individuals of different generations of a family, so a tendency to develop moles seems to be inherited, but the inheritance pattern is not well understood.Most moles occur on parts of the body that are exposed to the sun (ultraviolet radiation), and the number of moles an individual has may increase after extended time in the sun. Moles usually begin to occur in childhood. These moles are called acquired melanocytic nevi (and include the subtype epidermal nevus). It is common for new moles to appear during times when hormone levels change, such as adolescence and pregnancy. During an individual’s lifetime, moles may change in appearance; hair may grow out of them, and they can change in size and shape, darken, fade, or disappear. Infants and the elderly tend to have the fewest moles.
Sometimes, moles are present at birth or develop during infancy. These moles, which are called congenital nevi, are almost always benign. Rarely, a very large mole, called a giant congenital melanocytic nevus, is present at birth. In rare cases, the most serious type of skin cancer (called melanoma) may develop in this type of mole. Large, irregularly shaped and colored moles called dysplastic nevi or atypical moles can occur at any age. Although not common, they tend to be numerous, and they increase a person’s risk of melanoma. Heredity contributes to the development of dysplastic nevi and to having a higher-than-average number of benign moles. Spending a lot of time in the sun can also increase the number of moles a person has. However, moles are often found on areas of the body that are not exposed, which suggests that factors other than ultraviolet radiation from the sun, perhaps hormones or other biologic processes, are involved in triggering the development of acquired melanocytic nevi and dysplastic nevi.
Although the genetics of melanoma has been widely studied, much less is known about genes involved in the development of benign moles. Variations in several genes, including FGFR3, PIK3CA, HRAS, and BRAF, are involved with benign moles. The most-studied of these is the BRAF gene. A variant in BRAF leads to the production of an altered protein that causes melanocytes to aggregate into moles. This altered protein also triggers the production of a tumor-suppressor protein called p15 that stops moles from growing too big. In rare cases, BRAF gene variants together with loss (deletion) of the CDKN2A gene causes a lack of p15, which creates the potential for mole cells to grow uncontrollably and become cancerous (malignant). The formation of cancer is increasingly likely when combined with environmental factors, such as cell damage caused by ultraviolet radiation exposure.In susceptible individuals (those with fair skin, light hair, skin that burns instead of tans, a family history of melanoma, and genetic risk factors such as deletion of or variants in the CDKN2A gene), ultraviolet radiation from repeated sun exposure can damage existing moles, increasing their risk of becoming malignant. Research has shown that individuals who have an abundance of moles are at an increased risk of melanoma. However, some people who are diagnosed with melanoma have few moles, and melanoma often develops in areas of the body that are not exposed to the sun. Researchers are working to identify additional susceptibility genes to better understand the genetics of moles and their relationship with cancer.