Low-Penetrance Variants and Susceptibility to Sporadic Malignant Melanoma

Although malignant melanoma (MM) is mainly a sporadic disease, about 3 to 15% of the cases may show familial aggregation [1, 2]. The diagnosis of melanoma in different members of the same families does indeed suggest there is a genetically-based hereditary predisposi‐ tion in a significant percentage of the cases. However, this predisposition has proven to be genetically heterogeneous. Only two high-penetrance genes had been described so far: CDKN2A and CDK4 [1]. Yet mutations in these genes are found in only 30–40% of melano‐ ma kindreds, indicating the existence of additional genes involved in melanoma predisposi‐ tion [1]. Also, common low-penetrance alleles of the human pigmentation MC1R gene have been implicated in melanoma predisposition as well [3-13]. More recently, several other pig‐ mentation genes, such as ASIP, TYR, TYRP1, SLC45A2 and OCA2 have also emerged as be‐ ing potentially important in both normal human pigmentation variation and in melanoma susceptibility [14-17].