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

Our plain-English summary of Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non-CDKN2A/CDK4 melanoma families, by T.P. Potjer, S. Bollen, A.J.E.M. Grimbergen, et al (International Journal of Cancer, 2019).

The study

• Authors: T.P. Potjer, S. Bollen, A.J.E.M. Grimbergen, R. van Doorn, N.A. Gruis, C.J. van Asperen, F.J. Hes, N. van der Stoep, Dutch Working Group for Clinical Oncogenetics
• Journal: International Journal of Cancer
• Published: 2019;144(10):2453-2464
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma-prone families. In our study we comprehensively characterized 488 melanoma cases from 451 non-CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom-designed targeted gene panel approach. We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n = 3 BAP1, n = 15 MITF p.E318K; diagnostic yield 4.0%). Among the three identified BAP1-families, there were no reported diagnoses of uveal melanoma or malignant mesothelioma. We additionally identified two potentially deleterious missense variants in the telomere maintenance genes ACD and TERF2IP, but none in the POT1 gene. MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88-4.68, p <0.001). Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found. We conclude that multigene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non-CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test.

© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

In plain English

This Dutch genetic study did not examine asbestos exposure. It concerned inherited risk of melanoma, and malignant mesothelioma appears only as one of the cancers linked to the BAP1 gene. The authors sequenced 30 established and candidate melanoma susceptibility genes in 488 people with melanoma from 451 Dutch families in which no mutation had been found in the CDKN2A or CDK4 genes. They found likely disease-causing variants in established genes in 18 of the 451 families (4.0%): 3 in BAP1 and 15 with the MITF p.E318K variant. None of the three BAP1 families reported uveal melanoma, malignant mesothelioma or renal cell carcinoma. Two possibly harmful variants were found in the ACD and TERF2IP genes, and none in POT1. MC1R 'R' variants were more common in the 478 members of the familial cutaneous melanoma subgroup than in 449 controls (odds ratio 3.67, 95% CI 2.88 to 4.68). Rare variants in the albinism gene OCA2 were found repeatedly. The authors concluded that multigene panel testing gives an additional 4% diagnostic yield in these families. They noted that co-segregation analysis was not possible in many families.

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 sequencing study using a custom targeted gene panel in a familial melanoma cohort, with comparison of MC1R variant frequencies against a control cohort
• Who was studied: 488 melanoma patients (cutaneous or uveal) from 451 Dutch families with at least one other affected relative and no known CDKN2A or CDK4 mutation. Most probands (446) had cutaneous melanoma. The control cohort was 449 adults sequenced at the Leiden University Medical Centre for a form of diabetes (MODY).
• Exposure: No asbestos or other environmental exposure was studied. The study examined inherited (germline) variants in 30 established and candidate melanoma susceptibility genes, including BAP1, MITF, POT1, ACD, TERF2IP, MC1R and OCA2.
• Main results:
  • The authors found (likely) pathogenic variants in established high- and medium-penetrance genes in 18 of 451 families (4.0%): 3 BAP1 and 15 MITF.
  • In the three BAP1 families, no uveal melanoma, malignant mesothelioma or renal cell carcinoma was reported. Possible BAP1-associated Spitz nevi were reported in two families, and basal cell carcinomas in one.
  • The MITF p.E318K variant was found in 15 probands (3.3%), at a frequency more than twice that of the Dutch reference population (MAF 0.015 versus 0.007 in GoNL).
  • Two potentially deleterious missense variants were found in ACD and TERF2IP. No potentially deleterious variants were found in POT1, and no patient carried the TERT promoter variant c.-57T>G.
  • In the familial cutaneous melanoma subgroup (478 individuals) compared with 449 controls, MC1R R variants were enriched (OR 3.67, 95% CI 2.88 to 4.68, p less than 0.001). r variants were also enriched (OR 1.53, 95% CI 1.22 to 1.91, p less than 0.001).
  • Nine potentially deleterious OCA2 variants were found, six of them previously reported in oculocutaneous albinism type 2. Two of these (V443I and N489D) were found in 17 and 7 individuals, at more than twice the Dutch reference frequency. Co-segregation results were ambiguous.
• The authors' conclusion: The authors concluded that multigene panel testing for familial melanoma gives an additional 4% diagnostic yield in non-CDKN2A/CDK4 families, and that BAP1 and MITF should be included in such a diagnostic test.
• Limitations the authors state:
  • Co-segregation analysis of variants was not possible in many families, mainly because Ethics Committee restrictions prevented re-contacting patients.
  • The inclusion criteria were not highly stringent.
  • No functional testing was performed on the BRIP1 missense variants, whose effect is largely unknown.

Topics

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

Related studies

• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition — K.A. Wadt, L.G. Aoude, et al. (2015)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors — M. Cheung, Y. Kadariya, et al. (2021)
• Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma — K.G. Ewens, E. Lalonde, et al. (2018)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)

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