Molecular Characterization of Melanoma Cases in Denmark Suspected of Genetic Predisposition

Abstract

Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.

Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non‐CDKN2A/CDK4 melanoma families

“…There is extensive literature on the association between MC1R R and r variants and sporadic melanoma in population‐based cohorts . In our ‘familial CM’ cases, we observed a high frequency of MC1R R variants in particular, a finding comparable to the results of a Danish high‐risk melanoma cohort . This suggests that these common risk variants also play a significant role in the familial setting.…”

“…31 A similar frequency, 3.4% (19/558) in familial cases, was found in a study from the United States, although it is unclear if these patients were all pre-screened for CDKN2A mutations. 32 Frequencies in various other cohorts range from 0 to 3%, 16,28,[33][34][35] with the lowest frequency (<1%) reported in familial cases from Italy. 17,36 In the Netherlands, diagnostic testing for the MITF p.E318K risk variant is now included in the default genetic work-up for familial CM and all carriers are offered regular dermatologic surveillance (regardless of the familial burden for CM).…”

“…Although CM itself is relatively common in BAP1 mutation carriers (13–18%), BAP1 mutations are rarely reported in CM families without these other cancers: a study by Njauw et al . detected only one BAP1 mutation in 193 CM families (0.5%), and a study by Wadt et al . found no BAP1 mutations in 133 high‐risk CM patients (of which 94 CM families ).…”

The Danish Melanoma Database

“…Data from the DMD have been used for epidemiological, clinical, genetic, pathological, and molecular studies 6,9–14. The recent study on the development in incidence is a good example of an epidemiological study with use of the data, and this allows for monitoring of the development in incidence and mortality (a study in preparation) over time 6.…”

“…The recent study on the development in incidence is a good example of an epidemiological study with use of the data, and this allows for monitoring of the development in incidence and mortality (a study in preparation) over time 6. Advanced molecular and pathology studies have used detailed information from the DMD and provided important new knowledge on tumor profiles and pathogenesis 11–14. In Denmark, we have unique possibilities for high-quality register-based scientific studies because all inhabitants are assigned a unique personal identification number (civil personal registration number).…”