Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition

Our plain-English summary of Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition, by K.A. Wadt, L.G. Aoude, L. Krogh, et al (PloS One, 2015).

The study

• Authors: K.A. Wadt, L.G. Aoude, L. Krogh, L. Sunde, A. Bojesen, K. Grønskov, N. Wartacz, J. Ek, M. Tolstrup-Andersen, M. Klarskov-Andersen, Å. Borg, S. Heegaard, J.F. Kiilgaard, T.V. Hansen, K. Klein, G. Jönsson, K.T. Drzewiecki, M. Dunø, N.K. Hayward, A.M. Gerdes
• Journal: PloS One
• Published: 2015;10(3):e0122662
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This Danish genetic study tested people suspected of inherited melanoma risk: skin melanoma families, people with early or multiple melanomas, and some with uveal (eye) melanoma. Asbestos was not studied; mesothelioma appeared only in some families' histories. 313 members of 220 families were newly recruited; earlier results from 107 melanoma and 9 pancreatic cancer families were added to CDKN2A and CDK4 analyses. Among 304 unrelated cases, 3.9% carried a harmful CDKN2A mutation; in families with four or more affected members, 23.5% did. Carriers' mean age at first melanoma was 42.8 years, versus 48.3 in other high-risk cases; their estimated risk by age 70 was 80%. BAP1 mutations were not found in skin-melanoma-only groups. They were found in 4 of 6 families with two or more eye melanoma cases, and in 2 of 5 families with skin melanoma and mesothelioma. The authors advised against routine BAP1 testing in skin melanoma families. They would reserve it for families with skin and eye melanoma or mesothelioma, and possibly kidney cancer. They noted that testing one member per family for CDKN2A and CDK4 may have missed mutations.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genetic (molecular) study of high-risk melanoma cases and families, testing CDKN2A, CDK4, BAP1, MC1R and MITF (p.E318K)
• Who was studied: The newly recruited cohort was 313 members of 220 Danish families. Most were identified through the Danish melanoma registry and contacted in 2011–13; others came from genetic-counselling referrals and previously counselled dense melanoma families. Participants included people with family histories of cutaneous melanoma, early-onset melanoma or multiple primary melanomas. Cancer information from 107 previously tested cutaneous melanoma families and 9 pancreatic cancer families was added to the CDKN2A and CDK4 analyses. BAP1 was also tested in uveal melanoma cases and families, and in families with mesothelioma.
• Exposure: No environmental exposure was measured. The study examined inherited variants in CDKN2A, CDK4, MC1R and MITF in participants, and BAP1 in a subset. Asbestos was not studied.
• Main results:
  • 13 of 327 cases with early-onset cutaneous melanoma or multiple primary melanomas carried CDKN2A mutations
  • Among 304 unrelated melanoma cases suspected of hereditary predisposition, a pathogenic CDKN2A mutation was found in 3.9%
  • CDKN2A mutations were found in 5.6% of families with 3 melanoma cases and in 23.5% of families with 4 or more cases
  • Mean age at first melanoma was 42.8 years in CDKN2A mutation carriers versus 48.3 years in non-carriers, which the authors reported as significantly younger
  • Estimated penetrance of cutaneous melanoma at age 70 in CDKN2A mutation carriers was 80%
  • A CDK4 mutation (p.R24H) was found in 1 of 327 families
  • No BAP1 mutations were found in 10 cases of melanoma before age 40, 23 cases of multiple primary melanoma, or 94 melanoma families
  • Truncating BAP1 mutations were found in 4 of 6 families with 2 or more cases of uveal melanoma
  • Truncating BAP1 mutations were found in 2 of 5 families with cutaneous melanoma and mesothelioma. One of these families also had 3 uveal melanoma cases; the other had none.
  • MC1R R variants had a minor allele frequency of 0.389 in the melanoma cohort, almost twice that of the Danish population (0.204)
  • CDKN2A carriers with any MC1R variant had a hazard ratio of 3.39 for melanoma (95% CI 0.75–15.25, P = 0.112). The authors described this as a trend that was not statistically significant.
  • MITF p.E318K was found in 4 of 276 participants with cutaneous melanoma and in none of 20 with uveal melanoma, with an odds ratio of 3.16 compared with Danish controls
• The authors' conclusion: The authors recommended that BAP1 testing not be conducted routinely in cutaneous melanoma families. They would reserve it for families with cutaneous and uveal melanoma, or mesothelioma, and possibly also families with renal cell carcinoma.
• Limitations the authors state:
  • Uveal melanoma patients were not recruited systematically
  • Only one person per family was tested for CDKN2A and CDK4, so mutations in some families may have been missed
  • The results are not sufficient to exclude pancreatic cancer as part of the phenotype in Danish CDKN2A carriers

Topics

Medical terms in this study, explained in our Lexicon: CDKN2A, BAP1, Germline Mutation, Mesothelioma.

Related studies

• Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non-CDKN2A/CDK4 melanoma families — T.P. Potjer, S. Bollen, et al. (2019)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Ocular melanoma and the BAP1 hereditary cancer syndrome: implications for the dermatologist — L.M. Martorano, R.R. Winkelmann, et al. (2014)
• Clinical Implications of Real-time Integrative Sequencing in Management of Patients With Suspected Germline BAP1 Mutations — S. Sengupta, A.C. Weyand, et al. (2019)
• A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma — K.A. Wadt, L.G. Aoude, et al. (2015)

Browse more research in PloS One, or return to medical research.