Cutaneous melanoma (CM) sometimes runs in families in which there is an inherited mutation in a single ‘high penetrance’ gene, but in the general population predisposition is governed by several ‘low penetrance’ genes. Genome-wide association studies (GWAS) have identified >40 low penetrance CM susceptibility loci, the majority of which are related to well characterised CM risk phenotypes, including pigmentation: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and TYRP1; naevus development: MTAP/CDKN2A, PLA2G6, and IRF4; tanning response: RIPK5, PPARGC1B, and ATP11A; and telomere maintenance: TERC, TERT, and POT1. Many other loci have been identified, including: ATM, AGR3, BACH2, CASP8, CCND1, CDH1, CDKAL1, FTO, MPHOSPH6, MX2, PARP1, RAD23B, RAPGEF1, SETDB1 and TP53, which suggest a number of additional pathways involved in melanoma susceptibility. The majority of lead SNPs are located in putative gene enhancers for melanocytes or their paracrine regulators, keratinocytes.
High penetrance germline mutations in the CDKN2A and CDK4 genes account for susceptibility in ~40% of CM families, while mutations in the CDK4, MITF, TERT, POT1, ACD and TERF2IP genes are rare, each occurring in <1-2% of CM families. The latter four genes implicate telomere dysregulation as a major risk pathway for familial melanoma. Additionally, mutations in BAP1 have been associated with predisposition to both CM and uveal melanoma (UM), as well as susceptibility to mesothelioma and a range of other cancers. BAP1 is the most well-documented high penetrance UM gene, but is responsible for susceptibility in only ~5% of UM families. Germline mutations in CDKN2A and BRCA2 account for <1% of all susceptibility to UM. The genetic mutations underlying predisposition in the majority of CM and UM families is unknown.