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Importance: Despite the unquestioned relationship of UV radiation (UVR) exposure and melanoma development, UVR-independent development of melanoma has only recently been described in mice. These findings in mice highlight the importance of the genetic background of the host and could be relevant for preventive measures in humans., Objective: To study the role of the melanocortin-1 receptor (MC1R) and melanoma risk independently from UVR in a clinical setting., Design, Setting, and Participants: Hospital-based case-control study, including genetic testing, questionnaires, and physical data (Molecular Markers of Melanoma Study data set) including 991 melanoma patients (cases) and 800 controls., Main Outcomes and Measures: Association of MC1R variants and melanoma risk independent from sun exposure variables., Results: The 1791 participants included 991 with a diagnosis of melanoma and 800 control patients (mean [SD] age, 59.2 [15.6] years; 50.5% male). Compared with wild-type carriers, carriers of MC1R variants were at higher melanoma risk after statistically adjusting for previous UVR exposure (represented by prior sunburns and signs of actinic skin damage identified by dermatologists), age, and sex compared with wild-type carriers (≥2 variants, OR, 2.13 [95% CI, 1.66-2.75], P < .001; P for trend <.001). After adjustment for sex, age, sunburns in the past, and signs of actinic skin damage, the associations remained significant (OR, 1.65 [95% CI, 1.02-2.67] for R/R, OR, 2.63 [95% CI, 1.82-3.81] for R/r; OR, 1.83 [95% CI, 1.36-2.48] for R/0; and OR, 1.50 [95% CI, 1.01-2.21] for r/r, with P values ranging from <.001 to .04 when adjusted for facial actinic skin damage; OR, 2.36 [95% CI, 1.62-3.43] for R/r; and OR, 1.47 [95% CI, 1.08-1.99] for R/0 with P values ranging from <.001 to .01 when adjusted for dorsal actinic skin damage; and OR, 2.54 [95% CI, 1.76-3.67] for R/r, OR, 1.75 [95% CI, 1.30-2.36] for R/0; and OR, 1.50 [95% CI, 1.02-2.20] for r/r with P values ranging from <.001 to .04 when adjusted for actinic skin damage on the hands)., Conclusions and Relevance: Carriers of MC1R variants were at increased melanoma risk independent of their sun exposure. Further studies are required to elucidate the causes of melanoma development in these individuals.

Background: Risk of melanoma is determined by genetic and exogenous factors. Only a few studies have included both characteristics in a comprehensive multivariable analysis., Objectives: To find determinants of patients at high risk of melanoma in Austria, including phenotype, genotype and lifestyle characteristics in comprehensive analyses., Methods: In total, 1668 patients with melanoma from the M3 case-control study were studied. Overall, 567 participants were sequenced for CDKN2A, 232 for CDK4, 123 for MITF encoding the variant E318K and 964 for MC1R., Results: Patients with melanoma with a positive family history (n = 190, 11·6%), multiple primary melanomas (n = 261, 15·7%) and younger age (< 50 years, n = 675, 40·5%) were defined as being at high risk. All other patients with melanoma were defined as the reference group. We found significant differences between those two groups and between the high-risk subgroups (positive family history, multiple primary melanomas and younger age). Pigmentation phenotype was associated with the high-risk group in general (childhood freckling, odds ratio 1·46, P = 0·007; blond/reddish hair colour, odds ratio 1·43, P = 0·011). Patients with a positive family history and patients with early-onset disease were similar regarding both their phenotypic characteristics and external factors. Established high-risk mutations in CDKN2A were found in cases with a positive family history (n = 12) or multiple melanomas (n = 2). Moreover, we found three patients carrying the MITF p.E318K variant, two with a CDK4 variant and seven with nonsynonymous MC1R variants with undescribed biological significance, of which four were predicted as damaging., Conclusions: Austrian patients could represent a reservoir for novel genetic variants. Further investigation of populations in Central and Eastern Europe might reveal more novel and disease-relevant variants., (© 2016 British Association of Dermatologists.)

CDKN2A is the most prominent familial melanoma gene, with mutations occurring in up to 40% of the families. Numerous mutations in the gene are known, several of them representing regional founder mutations. We sought to determine, for the first time, germline mutations in CDKN2A in Austria to identify novel mutations. In total, 700 individuals (136 patients with a positive family history and 164 with at least two primary melanomas as the high-risk groups; 200 with single primary melanomas; and 200 healthy individuals as the control groups) were Sanger sequenced for CDKN2A exon 1α, 1β, and 2. The 136 patients with affected relatives were also sequenced for CDK4 exon 2. We found the disease-associated mutations p.R24P (8×), p.N71T (1×), p.G101W (1×), and p.V126D (1×) in the group with affected relatives and p.R24P (2×) in the group with several primary melanomas. Furthermore, we discovered four mutations of unknown significance, two of which were novel: p.A34V and c.151-4 G>C, respectively. Computational effect prediction suggested p.A34V as conferring a high risk for melanoma, whereas c.151-4 G>C, although being predicted as a splice site mutation by MutationTaster, could not functionally be confirmed to alter splicing. Moreover, computational effect prediction confirmed accumulation of high-penetrance mutations in high-risk groups, whereas mutations of unknown significance were distributed across all groups. p.R24P is the most common high-risk mutation in Austria. In addition, we discovered two new mutations in Austrian melanoma patients, p.A34V and c.151-4 G>C, respectively.

According to the prevailing multistep model of melanoma development, oncogenic BRAF or NRAS mutations are crucial initial events in melanoma development. It is not known whether melanocytic nevi that are found in association with a melanoma are more likely to carry BRAF or NRAS mutations than uninvolved nevi. By laser microdissection we were able to selectively dissect and genotype cells either from the nevus or from the melanoma part of 46 melanomas that developed in association with a nevus. In 25 cases we also genotyped a control nevus of the same patients. Available tissue was also immunostained using the BRAF(V600E)-mutation specific antibody VE1. The BRAF(V600E) mutation was found in 63.0% of melanomas, 65.2% of associated nevi and 50.0% of control nevi. No significant differences in the distribution of BRAF or NRAS mutations could be found between melanoma and associated nevi or between melanoma associated nevi and control nevi. In concordant cases immunohistochemistry showed a higher expression (intensity of immunohistochemistry) of the mutated BRAF(V600E)-protein in melanomas compared to their associated nevi. In this series the presence of a BRAF- or NRAS mutation in a nevus was not associated with the risk of malignant transformation. Our findings do not support the current traditional model of stepwise tumor progression.