Background BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome.DesignTo characterize BAP1's contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds.ResultsGermline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition.ConclusionGermline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive BAP1 inactivation.

In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes.

Familial melanoma accounts for approximately a tenth of all melanoma cases. The most commonly known melanoma susceptibility gene is the highly penetrant CDKN2A (p16INK4a) locus, which is transmitted in an autosomal dominant fashion and accounts for approximately 20-50 % of familial melanoma cases. Mutated p16INK4a shows impaired capacity to inhibit the cyclin D1-CDK4 complex, allowing for unchecked cell cycle progression. Mutations in the second protein coded by CDKN2A, p14ARF, are much less common and result in proteasomal degradation of p53 with subsequent accumulation of DNA damage as the cell progresses through the cell cycle without a functional p53-mediated DNA damage response. Mutations in CDK4 that impair the inhibitory interaction with p16INK4a also increase melanoma risk but these mutations are extremely rare. Genes of the melanin biosynthetic pathway, including MC1R and MITF, have also been implicated in melanomagenesis. MC1R variants were traditionally thought to increase risk for melanoma secondary to intensified UV-mediated DNA damage in the setting of absent photoprotective eumelanin. Accumulation of pheomelanin, which appears to have a carcinogenic effect regardless of UV exposure, may be a more likely mechanism. Impaired SUMOylation of the E318K variant of MITF results in increased transcription of genes that confer melanocytes with a pro-malignant phenotype. Mutations in the tumor suppressor BAP1 enhance the metastatic potential of uveal melanoma and predispose to cutaneous/ocular melanoma, atypical melanocytic tumors, and other internal malignancies (COMMON syndrome). Genome-wide association studies have identified numerous low-risk alleles. Although several melanoma susceptibility genes have been identified, risk assessment tools have been developed only for the most common gene implicated with hereditary melanoma, CDKN2A. MelaPRO, a validated model that relies on Mendelian inheritance and Bayesian probability theories, estimates carrier probability for CDKN2A and future risk of melanoma taking into account a patient's family and past medical history of melanoma. Genetic testing for CDKN2A mutations is currently available but the Melanoma Genetics Consortium recommends offering such testing to patients only in the context of research protocols because clinical utility is uncertain.

Background The penetrance of CDKN2A mutations is subject to geographic and latitudinal variation and is presumably dictated by UVR exposure and possibly other co-inherited genetic factors. The frequency of mutations increases with the number of family members affected and the number of primary tumors and also fluctuates with geography. Up to date, little is known about the prevalence of CDKN2A mutations in melanoma patients from Greece. Objective To characterize the frequency of CDKN2A and CDK4 mutations in a hospital-based population of Greek patients with melanoma. Methods Three-hundred and four consecutive single primary melanoma (SPM), 9 familial melanomas (FM) and 7 multiple primary melanoma cases (MPM) were assessed for sequence variants in exons 1α, 1β and 2 of CDKN2A and exon 2 of CDK4. Results Germline CDKN2A mutations were detected in 10 of 304 SPM (3.29%), in 4 of 7 MPM (57.0%) and in 2 of 9 FM (22.2%) cases. The most common mutation was a Northern European allele (p16 p.R24P) detected in 8 individuals. Five previously unreported CDKN2A variants were also identified: −34G>C, c.41_43delins20bp, c.301G>C(p.G101R), c.301G>A(p.G101E) and c.296_297insGACC. We also describe the first report of a Cdk4 p.R24H substitution in a Greek family. Conclusions The Greek population appears to harbor a higher prevalence of CDKN2A mutation than other reported cohorts. This supports the notion that genetic susceptibility may play a stronger influence in a country with a relatively low incidence of melanoma. Furthermore, the identification of Northern European alleles suggests that gene migration may be responsible, in part, for the observed cases in Greece.