| 1. |
- Taylor, Nicholas J, et al.
(författare)
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Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT
- 2019
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Ingår i: Journal of the American Academy of Dermatology. - : Elsevier BV. - 0190-9622 .- 1097-6787. ; 81:2, s. 386-394
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of melanoma families and whether performance improvements can be achieved.METHODS: 2,116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CI) along with net reclassification indices (NRI) as performance metrics.RESULTS: MELPREDICT performed well (AUC=0.752; 95%CI: 0.730, 0.775), and GenoMELPREDICT performance was similar (AUC=0.748; 95% CI: 0.726, 0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (p<0.0001) in GenoMELPREDICT (AUC=0.772; 95%CI: 0.750, 0.793; NRI=0.40). Including phenotypic risk factors did not improve performance.CONCLUSION: The MELPREDICT model functioned well in a global dataset of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in counselling these patients towards genetic testing or cancer risk counselling.
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| 2. |
- Taylor, Nicholas J., et al.
(författare)
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Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families
- 2017
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 137:12, s. 2606-2612
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18–2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92–1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94–1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75–4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.
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| 3. |
- Helgadottir, Hildur, et al.
(författare)
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Phenocopies in melanoma-prone families with germ-line CDKN2A mutations
- 2018
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 20:9, s. 1087-1090
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Carriers of CDKN2A mutations have high risks of melanoma and certain other cancers. In this study we examined the occurrence of tumors among CDKN2A wild type (wt) members of melanoma-prone families with CDKN2A mutations. Methods: Swedish and US melanoma-prone families with CDKN2A mutations were included. Data was collected on tumors diagnosed among family members. Among the CDKN2A mutated families, members with CDKN2A wt status who were diagnosed with melanoma were designated phenocopies. Results: Of patients with melanoma in the CDKN2A mutated families (n = 266), 7.1%, were seen among members with CDKN2A wt status (phenocopy rate). Among the CDKN2A wt family members of the CDKN2A mutated families (n = 256), 7.4% were diagnosed with melanoma. The prospective relative risk for melanomas was significantly higher among the CDKN2A wt subjects compared with population-based controls (7.4 (95% confidence interval 1.7–33.2)), while no elevated risks of nonmelanoma cancers were seen and their offspring did not have significantly elevated risks of melanoma or other cancers. Conclusion: Members of CDKN2A mutation carrying families who test negative for their family’s mutation have moderately increased risk for melanoma and should, in addition to being considered for continuing dermatologic surveillance, be encouraged to follow sun safety recommendations and practice skin self-exams.
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| 4. |
- Yang, Muyi, et al.
(författare)
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Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma
- 2022
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 24:1, s. 157-169
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: More than half of the familial cutaneous melanomas have unknown genetic predisposition. This study aims at characterizing a novel melanoma susceptibility gene. Methods: We performed exome and targeted sequencing in melanoma-prone families without any known melanoma susceptibility genes. We analyzed the expression of candidate gene DENND5A in melanoma samples in relation to pigmentation and UV signature. Functional studies were carried out using microscopic approaches and zebrafish model. Results: We identified a novel DENND5A truncating variant that segregated with melanoma in a Swedish family and 2 additional rare DENND5A variants, 1 of which segregated with the disease in an American family. We found that DENND5A is significantly enriched in pigmented melanoma tissue. Our functional studies show that loss of DENND5A function leads to decrease in melanin content in vitro and pigmentation defects in vivo. Mechanistically, harboring the truncating variant or being suppressed leads to DENND5A losing its interaction with SNX1 and its ability to transport the SNX1-associated vesicles from melanosomes. Consequently, untethered SNX1-premelanosome protein and redundant tyrosinase are redirected to lysosomal degradation by default, causing decrease in melanin content. Conclusion: Our findings provide evidence of a physiological role of DENND5A in the skin context and link its variants to melanoma susceptibility.
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| 5. |
- Yang, Xiaohong R., et al.
(författare)
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Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations
- 2016
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 135:11, s. 1241-1249
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Tidskriftsartikel (refereegranskat)abstract
- The risk of pancreatic cancer (PC) is increased in melanoma-prone families but the causal relationship between germline CDKN2A mutations and PC risk is uncertain, suggesting the existence of non-CDKN2A factors. One genetic possibility involves patients having mutations in multiple high-risk PC-related genes; however, no systematic examination has yet been conducted. We used next-generation sequencing data to examine 24 putative PC-related genes in 43 PC patients with and 23 PC patients without germline CDKN2A mutations and 1001 controls. For each gene and the four pathways in which they occurred, we tested whether PC patients (overall or CDKN2A+ and CDKN2A− cases separately) had an increased number of rare nonsynonymous variants. Overall, we identified 35 missense variants in PC patients, 14 in CDKN2A+ and 21 in CDKN2A− PC cases. We found nominally significant associations for mismatch repair genes (MLH1, MSH2, MSH6, PMS2) in all PC patients and for ATM, CPA1, and PMS2 in CDKN2A− PC patients. Further, nine CDKN2A+ and four CDKN2A− PC patients had rare potentially deleterious variants in multiple PC-related genes. Loss-of-function variants were only observed in CDKN2A− PC patients, with ATM having the most pathogenic variants. Also, ATM variants (n = 5) were only observed in CDKN2A− PC patients with a family history that included digestive system tumors. Our results suggest that a subset of PC patients may have increased risk because of germline mutations in multiple PC-related genes.
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