Update in genetic susceptibility in melanoma

Abstract

Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual.

Keywords: Melanoma; breast cancer 1 associated protein 1 (BAP1); cyclin-dependent kinase 4 (CDK4); cyclin-dependent kinase inhibitor 2A (CDKN2A); familial melanoma; genetic counseling; melanoma susceptibility; protection of telomeres 1 (POT1); telomere.

Figure 1

The figure represents the prevalence of mutations in high-risk melanoma susceptibility genes identified to date in melanoma-prone families. This figure includes the genetic information of 2,511 pedigrees: 487 CDKN2A, 17 CDK4, 24 BAP1, 1 CXC, 1 TERT, 12 POT1, 6 ACD and 5 TERF2IP mutated pedigrees respectively, and 1,958 families with unknown mutation. The data used to prepare this figure was that reported in previous research articles (25-39). We have excluded information from the Goldstein et al.’s study (26), from the groups belonging to GenoMEL consortium that have published updated reports of CDKN2A mutations alone, to avoid duplicates. For all those groups that have reported different updates of their families over time, we have selected the most recent article or the one that included a greater number of families. CDKN2A, cyclin-dependent kinase inhibitor 2A; CDK4, cyclin-dependent kinase 4; BAP1, Breast cancer 1 (BRCA1) associated protein 1; TERT, telomerase reverse transcriptase; POT1, protection of telomeres 1.

Figure 2

Cell biology functions and pathways of the genes involved in melanoma susceptibility. In red all proteins encoded by known high risk melanoma susceptibility genes. (A) CDKN2A encodes two different proteins p16INK4a and p14ARF. p16INK4a is an inhibitor of the cyclinD1/CDK4 complex and induces the arrest of the cell cycle. When p16INK4a can perform its function correctly, if a cell is damaged it can induce senescence. However when CDKN2A is mutated, the cyclinD1/CDK4 complex is not inhibited and phosphorylated pRb, releasing E2F transcription factor that can induce a cell cycle progression. If a cell is damaged the release of E2F can favor an aberrant proliferation that can lead to tumor development. In the same way, when CDK4 is mutated, p16INK4a cannot interact with it and cannot inhibit the release of E2F. p14ARF in front of a damaged cell induces apoptosis through the p53 pathway. If p14ARF is mutated, MDM2 can promote p53 ubiquitination and p53 is degraded in the proteasome. Thus when a cell is damaged, the lack of activation of p53 can allow that cell to avoid apoptosis (21). (B) BAP1 is involved mainly in epigenetic and gene transcription regulation interacting with multiple partners (54). When BAP1 is mutated it cannot properly do its activity and this can lead to a dysregulation of gene transcription that can alter the proliferation controls. BAP1 has a tumor suppressor role, thus when a cell is damaged, mutant BAP1 cells can start proliferating in an aberrant way that can lead to the development of a tumor. (C) Telomeres form a protective structure at the ends of the chromosome (T-loop) that is covered by the shelterin complex (TERF2IP, TERF1, TERF2, TINF2, ACD and POT1). This complex also mediates the interaction between telomeres and the telomerase (TERT). Shelterin binds to the telomere through TERF1 and TERF2. POT1 binding to the single-stranded DNA overhang prevents access of telomerase to telomeres. When POT1 is unbound, the telomerase is able to extend telomeres. Furthermore when the telomeres are unprotected by the shelterin complex senescence and apoptosis can be induced. Mutations in genes lead to telomere dysregulation and can be involved in the development of a tumor when the cells are damaged (67-69,72-75). CDKN2A, cyclin-dependent kinase inhibitor 2A; CDK4, cyclin-dependent kinase 4; BAP1, Breast cancer 1 (BRCA1) associated protein 1; POT1, protection of telomeres 1.