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

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          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.

          Abstract

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          Germline mutations in CDKN2A are major contributors to familial melanoma. These mutations, however, are responsible for only 10 to 40 percent of genetic susceptibility in melanoma‐prone families. In this study, 30 established and candidate melanoma susceptibility genes were investigated for associations with the disease in patients from 451 non‐ CDKN2A/ CDK4 melanoma families. From the candidate gene panel, (likely) pathogenic variants in BAP1 and MITF were identified in several families, and potentially deleterious variants were identified in the shelterin complex genes ACD and TERF2IP. These genes appear to play a significant role in familial melanoma predisposition and are therefore promising candidates for incorporation into comprehensive genetic tests.

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          Most cited references31

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          Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

          Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours were microsatellite-stable, but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently-described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE exonuclease domain mutations.
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            International trends in the incidence of malignant melanoma 1953-2008--are recent generations at higher or lower risk?

            The incidence of cutaneous malignant melanoma has steadily increased over the past 50 years in predominately fair-skinned populations. This increase is reported to have leveled off recently in several Northern and Western European countries, Australia, New Zealand and in North America. We studied the global patterns and time trends in incidence of melanoma by country and sex, with a focus on and age- and cohort-specific variations. We analyzed the incidence data from 39 population-based cancer registries, examining all-ages and age-truncated standardized incidence rates of melanoma, estimating the annual percentage change and incidence rate ratios from age-period-cohort models. Incidence rates of melanoma continue to rise in most European countries (primarily Southern and Eastern Europe), whereas in Australia, New Zealand, the U.S., Canada, Israel and Norway, rates have become rather stable in recent years. Indications of a stabilization or decreasing trend were observed mainly in the youngest age group (25-44 years). Rates have been rising steadily in generations born up to the end of the 1940s, followed by a stabilization or decline in rates for more recently born cohorts in Australia, New Zealand, the U.S., Canada and Norway. In addition to the birth cohort effect, there was a suggestion of a period-related influence on melanoma trends in certain populations. Although our findings provide support that primary and secondary prevention can halt and reverse the observed increasing burden of melanoma, they also indicate that those prevention measures require further endorsement in many countries. Copyright © 2012 UICC.
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              MC1R variants, melanoma and red hair color phenotype: a meta-analysis.

              Melanocortin-1-receptor (MC1R) is one of the major genes that determine skin pigmentation. MC1R variants were suggested to be associated with red hair, fair skin, and an increased risk of melanoma. We performed a meta-analysis on the association between the 9 most studied MC1R variants (p.V60L, p.D84E, p.V92M, p.R142H, p.R151C, p.I155T, p.R160W, p.R163Q and p.D294H) and melanoma and/or red hair, fair skin phenotype. Eleven studies on MC1R and melanoma, and 9 on MC1R and phenotype were included in the analysis. The 7 variants p.D84E, p.R142H, p.R151C, p.I155T, p.R160W, p. R163Q and p.D294H were significantly associated with melanoma development, with ORs (95%CI) ranging from 1.42 (1.09-1.85) for p.R163Q to 2.45 (1.32-4.55) for p.I155T. The MC1R variants p.R160W and p.D294H were associated both with red hair and fair skin, while p.D84E, p.R142H, and p.R151C were strongly associated with red hair only- ORs (95%CI) ranged from 2.99 (1.51-5.91) for p.D84E to 8.10 (5.82-11.28) for p.R151C. No association with melanoma or phenotype was found for p.V60L and p.V92M variants. In conclusion this meta-analysis provided evidence that some MC1R variants are associated both with melanoma and phenotype, while other are only associated with melanoma development. These results suggest that MC1R variants could play a role in melanoma development both via pigmentary and non-pigmentary pathways. (c) 2008 Wiley-Liss, Inc.
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                Author and article information

                Contributors
                nvdstoep@lumc.nl
                Journal
                Int J Cancer
                Int. J. Cancer
                10.1002/(ISSN)1097-0215
                IJC
                International Journal of Cancer
                John Wiley & Sons, Inc. (Hoboken, USA )
                0020-7136
                1097-0215
                21 January 2019
                15 May 2019
                : 144
                : 10 ( doiID: 10.1002/ijc.v144.10 )
                : 2453-2464
                Affiliations
                [ 1 ] Department of Clinical Genetics Leiden University Medical Centre Leiden the Netherlands
                [ 2 ] Department of Dermatology Leiden University Medical Centre Leiden the Netherlands
                Author notes
                [*] [* ] Correspondence to: Nienke van der Stoep, PhD, Department of Clinical Genetics, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, the Netherlands, Tel.: 00‐31‐715269800, Fax: 00‐31‐715268276, E‐mail: nvdstoep@ 123456lumc.nl
                [†]

                Dutch Working Group for Clinical Oncogenetics: A. Wagner, L.E. van der Kolk, M.G. Ausems, T.A. Van Os, K.J, van Kaam, L. Spruijt, C.J. Dommering, P.C. van den Akker

                Author information
                https://orcid.org/0000-0002-3831-6022
                Article
                IJC31984
                10.1002/ijc.31984
                6590189
                30414346
                da92d84c-af23-42b5-a49f-5f378eeb639e
                © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 25 August 2018
                : 12 October 2018
                : 25 October 2018
                Page count
                Figures: 0, Tables: 6, Pages: 12, Words: 9307
                Funding
                Funded by: KWF Kankerbestrijding
                Award ID: #UL 2015‐7511 to TPP and NvdS and #UL 2012‐5489 to RvD, NAG and NvdS
                Categories
                Cancer Genetics and Epigenetics
                Cancer Genetics and Epigenetics
                Custom metadata
                2.0
                ijc31984
                15 May 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:24.06.2019

                Oncology & Radiotherapy
                familial melanoma,genetic susceptibility,gene panel sequencing,bap1,mitf,high‐penetrance genes,candidate susceptibility genes,oca2

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