Risk factors for melanoma development

Abstract

Melanoma incidence has risen over the last 30 years; however, whether this increase is entirely genuine or caused, in part, by increased screening, needs to be addressed. A large number of nevi is the strongest risk factor for melanoma across all Caucasian populations. Number of nevi is heritable with 60% of the variation in their number attributed to additive genetic effects. Fair hair and skin is also a heritable risk factor but the magnitude of the risk is much smaller than nevi. There are different ‘at-risk’ phenotypes leading to melanoma: high number of nevi or alternatively sun damage with solar keratoses, and these two phenotypes are usually mutually exclusive. This suggests different pathways leading to melanoma. Sun exposure is linked to melanoma with an increased melanoma incidence with decreasing latitude. However, this association is very complex and is not dose dependent. Similar to all cancers, melanoma can cluster in families. Between 20 and 40% of melanoma-prone families have mutations in the tumor-suppressor gene p16 or CDKN2A. These mutations only explain a small proportion of sporadic melanomas. New common low-penetrance melanoma genes associated with pigmentation and nevi counts have recently been discovered. As for many cancers, melanoma is likely to be caused by complex interactions between environmental factors and common low-penetrance genes. Once melanoma genetic risk factors are better understood, it will be possible to further investigate genetic environment interactions and assess the role of sun exposure more accurately. Somatic mutations in p16, p53, BRAF and c-kit are found in melanoma tumors and some of these somatic mutations may be useful to offer melanoma-targeted therapy.