| 1. |
- Helgadottir, Hildur, et al.
(författare)
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Germline CDKN2A Mutation Status and Survival in Familial Melanoma Cases
- 2016
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 108:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Germline mutations in CDKN2A have been associated with increased risk of melanoma and tobacco-related cancers in respiratory and upper digestive tissues. In CDKN2A wild-type (wt) melanoma families, other known high-risk, melanoma-predisposing mutations are rare, and no increased risk has been observed for nonskin cancers in this group. This study is the first to compare survival in germline CDKN2A mutated (mut) and nonmutated melanoma cases.METHODS: Melanoma-prone families participating in this study were identified through a nationwide predictive program starting in 1987. Information on cancer diagnoses (types, stages, and dates) and deaths (causes and dates) were obtained through the Swedish Cancer Registry and Cause of Death Registry. Kaplan Meier and Cox proportional hazards regression models were used to assess survival in CDKN2A(mut) (n = 96) and CDKN2A(wt) (n = 377) familial melanoma cases and in matched sporadic melanoma cases (n = 1042). All statistical tests were two-sided.RESULTS: When comparing CDKN2A(mut) and CDKN2A(wt) melanoma cases, after adjusting for age, sex, and T classification, CDKN2A(mut) had worse survival than melanoma (hazard ratio [HR] = 2.50, 95% confidence interval [CI] = 1.49 to 4.21) and than nonmelanoma cancers (HR = 7.77, 95% CI = 3.65 to 16.51). Compared with matched sporadic cases, CDKN2A(mut) cases had statistically significantly worse survival from both melanoma and nonmelanoma cancers while no differences in survival were seen in CDKN2A(wt) compared with sporadic cases.CONCLUSIONS: CDKN2A(mut) cases had statistically significantly worse survival than nonmelanoma cancers and, intriguingly, also from melanoma, compared with melanoma cases with no CDKN2A mutations. Further studies are required to elucidate possible mechanisms behind increased carcinogen susceptibility and the more aggressive melanoma phenotype in CDKN2A mutation carriers.
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| 2. |
- Helgadottir, Hildur, et al.
(författare)
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Melanoma Incidence and Mortality Trends in Sweden
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Ingår i: JAMA Dermatology. - 2168-6084.
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Over the past decades, many global regions have experienced a steady increase in the incidence of cutaneous melanoma. However, more recently, a downward trend has been observed in the younger age groups in Australia and the US. Yet, in Europe, none of the countries have reported any significant decline in melanoma incidence for any age group.OBJECTIVE: To assess melanoma incidence and mortality trends in Sweden, with a focus on individuals younger than the average age of melanoma onset.DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data on the national population from the Swedish Melanoma Registry and the Swedish Cancer Registry, which cover more than 99% of all primary invasive cutaneous melanomas diagnosed in the country. All patients diagnosed from 1990 to 2022 were included.MAIN OUTCOMES AND MEASURES: Incidence and mortality rates per 100 000 inhabitants were calculated for each year and shown as average annual rates for every 5-year period from 1990 to 2022. Joinpoint regression models were used to evaluate statistical significance of temporal trends and points of change.RESULTS: There were 34 800 primary invasive cutaneous melanomas (19 582 [56.3%] in females and 15 218 [43.7%] in males) reported in 33 324 individuals younger than 60 years (median [IQR] age, 48 [36-58] years) from 1990 to 2022. A consistent rise in melanoma incidence was observed among those 50 to 59 years old. The age groups from 20 to 29 years, 30 to 39 years, and 40 to 49 years showed an incidence peak in 2013 to 2015 followed by stable or significantly declining rates until 2022. In patients younger than 20 years, melanoma incidence remained low with no significant trends. There was also a significant decline in melanoma mortality among 30- to 59-year-old individuals, but not in those 60 years and older.CONCLUSIONS AND RELEVANCE: The findings of this cohort study showed a significant recent downward trend in both melanoma incidence and melanoma mortality in the age group 30 to 49 years in Sweden. The reasons for these declines are unclear but may include UV protection, public health campaigns, changing population demographics, and the introduction of effective melanoma treatment. None of these possibilities were evaluated; further study is needed.
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| 3. |
- Helgadottir, Hildur, et al.
(författare)
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Ökad kunskap om familjärt melanom och de bakomliggande generna
- 2017
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Ingår i: Läkartidningen. - 0023-7205. ; 2017:19, s. 900-903
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 5-10 % of all melanoma patients have close relatives with melanoma. 5-20% of melanoma families have germline mutations in the CDKN2A gene. Swedish CDKN2A mutation carriers have a young median age of onset of melanoma, increased risks of multiple primary melanoma and of tobacco-associated cancers in respiratory and upper digestive tissues, and also worse survival compared to non-carriers. In up to 80% of melanoma families no high risk melanoma associated germline mutations are found. In a few (non-Swedish) melanoma families, mutations in other genes have been found, including CDK4, TERT, POT1, ACD and TERF2IP. In some families with multiple cases of uveal and cutaneous melanoma (including a few Swedish families), mutations in the BAP1 gene have been found. In genes that regulate cellular pigmentation pathways, including MC1R, ASIP, IRF4, TYR, TYRP1 and OCA, there are different common variants that determine complexion traits, and those variants are also associated with different risks of melanoma. Members belonging to identified melanoma families require close follow-up with dermatologic exams. Individuals with known mutations in tumor suppressor genes such as CDKN2A and BAP1 require, in addition, follow up for other cancers.
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| 4. |
- Pissa, Maria, et al.
(författare)
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CDKN2A genetic testing in melanoma-prone families in Sweden in the years 2015–2020 : implications for novel national recommendations
- 2021
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Ingår i: Acta Oncologica. - : Taylor & Francis Group. - 0284-186X .- 1651-226X. ; 60:7, s. 888-896
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Tidskriftsartikel (refereegranskat)abstract
- Background: Inherited pathogenic variants (PVs) in the CDKN2A gene are among the strongest known risk factors for cutaneous melanoma. Carriers are at high risks to develop multiple primary melanomas and other cancers, in particular pancreatic cancer. In this study, the CDKN2A testing, carried out in Sweden in the years 2015–2020, was evaluated.Materials and methods: Included families had (1) three or more cases of melanoma and/or pancreatic cancer, (2) two melanomas in first-degree relatives, the youngest case <55 years or (3) individuals with three or more multiple primary melanomas, the first before the age of 55 years, and no other affected family members. The included families had at least one affected member that had been tested for CDKN2A PVs.Results: In total, 403 families were included, whereof 913 family members had been diagnosed with cutaneous melanoma and 129 with pancreatic cancer, 33 (8.2%) were found to have PVs in CDKN2A. Frequencies ranged from 0.9% in families with only two melanomas to 43.2% in families with three or more melanoma cases and pancreatic cancer (p < 0.001). The frequency of PVs ranged from 2.1% to 16.5% in families where the youngest case was ≥55 years or <35 years (p = 0.040). In families with or without CDKN2A PVs, 37.6% and 10.0% had melanoma cases that had died from melanoma, respectively (p < 0.001).Discussion: Significant differences were seen in the frequencies of CDKN2A PVs, dependent on numbers or age at diagnosis of melanomas and diagnoses of pancreatic cancers in the family. Further, melanoma cases belonging to families that tested positive for CDKN2A PVs had a significantly higher mortality. To summarize, the current evaluation shows that, with adequately selected criteria to guide genetic testing, CDKN2A PVs are identified at significant frequencies. Identification of carrier families is of importance to ensure that members are enrolled in a preventive surveillance program.
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