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BACKGROUND: Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action. METHODS: National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country. RESULTS: Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the 'who, what, when and where' of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the 'most important change' which would improve practice. CONCLUSIONS: This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels.
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União Europeia , Aconselhamento Genético , Neoplasias , Humanos , Aconselhamento Genético/legislação & jurisprudência , Neoplasias/genética , Testes Genéticos/legislação & jurisprudênciaRESUMO
Cascade genetic testing and surveillance reduce morbidity and mortality in Lynch syndrome. However, barriers to conveying information about genetic disorders within families result in low uptake of genetic testing. Provider-mediated interventions may increase uptake but raise legal and ethical concerns. We describe 30 years of national experience with cascade genetic testing combining family- and provider-mediated contact in Lynch syndrome families in the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Register. We aimed to estimate the added value of information letters to family members in Lynch syndrome families (provider-mediated contact) compared to family members not receiving such letters and thus relying on family-mediated contact. National clinical practice for cascade genetic testing, encompassing infrastructure, legislation, acceptance, and management of the information letters, is also discussed. Cascade genetic testing resulted in 7.3 additional tests per family. Uptake of genetic testing was 54.4% after family-mediated and 64.9% after provider-mediated contact, corresponding to an odds ratio of 1.8 (p < 0.001). The uptake of genetic testing was highest in the first year after diagnosis of Lynch syndrome in the family, with 72.5% tested after provider-mediated contact. In conclusion, the Danish model combining family- and provider-mediated contact can increase the effect of cascade genetic testing.
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Germline pathogenic variants associated with increased childhood mortality must be subject to natural selection. Here, we analyze publicly available germline genetic metadata from 4,574 children with cancer [11 studies; 1,083 whole exome sequences (WES), 1,950 whole genome sequences (WGS), and 1,541 gene panel] and 141,456 adults [125,748 WES and 15,708 WGS]. We find that pediatric cancer predisposition syndrome (pCPS) genes [n = 85] are highly constrained, harboring only a quarter of the loss-of-function variants that would be expected. This strong indication of selective pressure on pCPS genes is found across multiple lines of germline genomics data from both pediatric and adult cohorts. For six genes [ELP1, GPR161, VHL and SDHA/B/C], a clear lack of mutational constraint calls the pediatric penetrance and/or severity of associated cancers into question. Conversely, out of 23 known pCPS genes associated with biallelic risk, two [9%, DIS3L2 and MSH2] show significant constraint, indicating that they may monoallelically increase childhood cancer risk. In summary, we show that population genetic data provide empirical evidence that heritable childhood cancer leads to natural selection powerful enough to have significantly impacted the present-day gene pool.
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Neoplasias , Adulto , Humanos , Criança , Neoplasias/genética , Predisposição Genética para Doença , Pool Gênico , Mutação , Mutação em Linhagem GerminativaRESUMO
TINF2 encodes the TINF2 protein, which is a subunit in the shelterin complex critical for telomere regulation. Three recent studies have associated six truncating germline variants in TINF2 that have previously been associated with a cancer predisposition syndrome (CPS) caused by elongation of the telomeres. This has added TINF2 to the long telomere syndrome genes, together with other telomere maintenance genes such as ACD, POT1, TERF2IP, and TERT. We report a clinical study of 102 Danish patients with multiple primary melanoma (MPM) in which a germline truncating variant in TINF2 (p.(Arg265Ter)) was identified in four unrelated participants. The telomere lengths of three variant carriers were >90% percentile. In a routine diagnostic setting, the variant was identified in two more families, including an additional MPM patient and monozygotic twins with thyroid cancer and other cancer types. A total of 10 individuals from six independent families were confirmed carriers, all with cancer history, predominantly melanoma. Our findings suggest a major role of TINF2 in Danish patients with MPM. In addition to melanoma, other cancers in the six families include thyroid, renal, breast, and sarcoma, supporting a CPS in which melanoma, thyroid cancer, and sarcoma predominate. Further studies are needed to establish the full spectrum of associated cancer types and characterize lifetime cancer risk in carriers.
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Melanoma , Neoplasias Primárias Múltiplas , Sarcoma , Neoplasias da Glândula Tireoide , Humanos , Melanoma/genética , Síndrome , Dinamarca/epidemiologia , Proteínas de Ligação a Telômeros/genéticaRESUMO
BACKGROUND: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse. METHODS: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes. RESULTS: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01). CONCLUSION: We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.
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Síndrome de Beckwith-Wiedemann , Neoplasias Renais , Tumor de Wilms , Masculino , Feminino , Humanos , Proteína 7 com Repetições F-Box-WD/genética , Macrossomia Fetal/genética , Impressão Genômica , Tumor de Wilms/genética , Genótipo , Síndrome de Beckwith-Wiedemann/patologia , Metilação de DNA/genética , Suscetibilidade a Doenças , Neoplasias Renais/genética , Células Germinativas/patologiaRESUMO
The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance.
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Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Humanos , Pessoa de Meia-Idade , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA/genética , Testes Genéticos , Predisposição Genética para Doença , Proteínas de Ligação a DNA/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa , Instabilidade de MicrossatélitesRESUMO
OBJECTIVE: The diagnosis of cancer in a child is a profoundly stressful experience. The impact on parents' somatic health, including lifestyle-related diseases, however, is unresolved. This paper assesses parents' risk of hospitalization with somatic disease after a child's cancer diagnosis. METHODS: We conducted a nationwide population- and register-based study with parents of all children under age 20 diagnosed with cancer in Denmark between 1998 and 2013 and parents of cancer-free children, matched (1:10) on child's age and family type. We estimated HR with 95% CI in Cox proportional hazard models for 13 major International Classification of Diseases-10 disease groups, selected stress- and lifestyle-related disease-groups, and investigated moderation by time since diagnosis, parental sex, and cancer type. RESULTS: Among n = 7797 parents of children with cancer compared with n = 74,388 parents of cancer-free children (51% mothers, mean age 42), we found no overall pattern of increased risk for 13 broad disease groups. We found increases in digestive system diseases (HR 1.06, 95% CI 1.01-1.12), genitourinary system diseases (HR 1.08, 95% CI 1.02-1.14), and neoplasms (HR 1.20, 95% CI 1.13-1.27), the latter attributable mostly to increased rates of tobacco-related cancers and mothers' diet-related cancers. CONCLUSIONS: This is the first attempt to document the impact of childhood cancer on parents' somatic health. With the exception of increased risk for neoplasms, likely due to shared genetic or lifestyle factors, our findings offer the reassuring message, that the burden of caring for a child with cancer does not in general increase parents' risk for somatic diseases.
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Neoplasias , Pais , Adulto , Criança , Estudos de Coortes , Feminino , Hospitalização , Humanos , Mães , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Adulto JovemRESUMO
Hereditary polyposis syndromes are characterized by a large number and/or histopathologically specific polyps in the gastrointestinal tract and a high risk of both colorectal cancer and extracolonic cancer at an early age. While the genes responsible for some of the syndromes, eg, APC in familial adenomatous polyposis and STK11 in Peutz-Jeghers syndrome, have been known for decades, novel genetic causes have recently been detected that have shed light on the broader clinical spectrum of syndromes. Genetic diagnoses are important because they can facilitate a personalized surveillance program. Furthermore, at-risk members of the patient's family can be tested and enrolled in surveillance as needed. In some cases, prenatal diagnostics should be offered. In this paper, we describe the development in germline genetics of the hereditary polyposis syndromes over the last 10-12 years, their clinical characteristics, as well as how to implement genetic analyses in the diagnostic pipeline.
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BACKGROUND: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. METHODS: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. RESULTS: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. CONCLUSIONS: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.
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Melanoma , Neoplasias Cutâneas , Queimadura Solar , Humanos , Melanoma/epidemiologia , Melanoma/prevenção & controle , Estudos Retrospectivos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/prevenção & controle , Queimadura Solar/epidemiologia , Queimadura Solar/prevenção & controle , Protetores Solares/uso terapêuticoRESUMO
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 families with melanoma and whether performance improvements can be achieved. METHODS: In total, 2116 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 (CIs) along with net reclassification indices (NRIs) 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 < .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 data set 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 directing these patients to receive genetic testing or cancer risk counseling.
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Inibidor p16 de Quinase Dependente de Ciclina/genética , Predisposição Genética para Doença , Modelos Logísticos , Melanoma/genética , Neoplasias Pancreáticas , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Criança , Testes Genéticos , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Internacionalidade , Pessoa de Meia-Idade , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Fenótipo , Valor Preditivo dos Testes , Probabilidade , Curva ROC , Fatores de Risco , Adulto JovemRESUMO
DDX41 has recently been identified as a new autosomal dominantly inherited cancer predisposition syndrome causing increased risk of adult onset acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We report for the first time compound heterozygote germline missense DDX41 mutations located in the DEAD-box domain, identified in two siblings by exome sequencing. Both siblings have slight dysmorphic findings, psychomotor delays and intellectual disability, and one developed blastic plasmacytoid dendritic cell neoplasm (BPDCN) at age five. RNA-sequencing of bone marrow showed DDX41 expression including both mutations. However, the allele fraction of p.Pro321Leu accounted for 96% in the RNA-sequencing indicating this mutation to be the more significant variant. Exome sequencing of the leukemic blasts identified no additional known driver mutations. There is no pattern indicating autosomal dominantly inherited cancer predisposition in the family, but the father has sarcoidosis, which has been associated with heterozygous DDX41 mutation. We propose that bi-allelic mutations in DDX41 could potentially be a new cancer predisposition syndrome associated with delayed psychomotor development.
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RNA Helicases DEAD-box/genética , Leucemia Mieloide/genética , Mutação de Sentido Incorreto , Pré-Escolar , Células Dendríticas , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Exoma , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Leucemia Mieloide/complicações , Linhagem , Gravidez , Transtornos Psicomotores/complicações , Transtornos Psicomotores/genética , SíndromeRESUMO
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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Inibidor de Quinase Dependente de Ciclina p18/genética , Mutação em Linhagem Germinativa , Melanoma/genética , Nevo/genética , Neoplasias Cutâneas/genética , Inibidor p16 de Quinase Dependente de Ciclina , Análise Mutacional de DNA , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Nevo Pigmentado/genética , Razão de Chances , Fenótipo , Sistema de Registros , Melanoma Maligno CutâneoAssuntos
Inibidor de Quinase Dependente de Ciclina p18/genética , Predisposição Genética para Doença/epidemiologia , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adulto , Idoso , Biópsia por Agulha , Estudos de Coortes , Inibidor p16 de Quinase Dependente de Ciclina , Bases de Dados Factuais , Feminino , Humanos , Imuno-Histoquímica , Incidência , Masculino , Melanoma/epidemiologia , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Prognóstico , Medição de Risco , Neoplasias Cutâneas/epidemiologia , Melanoma Maligno CutâneoRESUMO
Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.
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Predisposição Genética para Doença/genética , Melanoma/genética , Regiões Promotoras Genéticas , Telomerase/genética , Adulto , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genética , Neoplasias Cutâneas , Adulto Jovem , Melanoma Maligno CutâneoRESUMO
Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence of heritable melanoma risk genes is an important component of disease occurrence. Susceptibility for some families is due to mutation in one of the known high penetrance melanoma predisposition genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP and TERT. However, despite such mutations being implicated in a combined total of approximately 50% of familial melanoma cases, the underlying genetic basis is unexplained for the remainder of high-density melanoma families. Aside from the possibility of extremely rare mutations in a few additional high penetrance genes yet to be discovered, this suggests a likely polygenic component to susceptibility, and a unique level of personal melanoma risk influenced by multiple low-risk alleles and genetic modifiers. In addition to conferring a risk of cutaneous melanoma, some 'melanoma' predisposition genes have been linked to other cancers, with cancer clustering observed in melanoma families at rates greater than expected by chance. The most extensively documented association is between CDKN2A germ line mutations and pancreatic cancer, and a cancer syndrome including cutaneous melanoma, uveal melanoma and mesothelioma has been proposed for BAP1 germ line mutations. Other medium to high penetrance melanoma predisposition genes have been associated with renal cell carcinoma (MITF, BAP1) and glioma (POT1). These associations between melanoma and other cancers hint at the possibility of common pathways for oncogenesis, and better knowledge of these pathways may improve understanding of the genetic basis underpinning familial melanoma. It is likely that 'melanoma' risk genes will impact on mutation screening and genetic counselling not only for melanoma but also a range of other cancers.
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Estudos de Associação Genética , Predisposição Genética para Doença , Melanoma/genética , Animais , Meio Ambiente , Epistasia Genética , Interação Gene-Ambiente , Humanos , Melanoma/epidemiologia , Melanoma/etiologia , Melanoma/patologia , Mutação , Neoplasias/epidemiologia , Neoplasias/etiologia , Penetrância , Fenótipo , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
The incidence of melanoma in Denmark has immensely increased over the last 10 years making Denmark a high risk country for melanoma. In the last two decades multiple public campaigns have sought to increase the awareness of melanoma. Family history of melanoma is a known major risk factor but previous studies have shown that self-reported family history of melanoma is highly inaccurate. These studies are 15 years old and we wanted to examine if a higher awareness of melanoma has increased the accuracy of self-reported family history of melanoma. We examined the family history of 181 melanoma probands who reported 199 cases of melanoma in relatives, of which 135 cases where in first degree relatives. We confirmed the diagnosis of melanoma in 77% of all relatives, and in 83% of first degree relatives. In 181 probands we validated the negative family history of melanoma in 748 first degree relatives and found only 1 case of melanoma which was not reported in a 3 case melanoma family. Melanoma patients in Denmark report family history of melanoma in first and second degree relatives with a high level of accuracy with a true positive predictive value between 77 and 87%. In 99% of probands reporting a negative family history of melanoma in first degree relatives this information is correct. In clinical practice we recommend that melanoma diagnosis in relatives should be verified if possible, but even unverified reported melanoma cases in relatives should be included in the indication of genetic testing and assessment of melanoma risk in the family.
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Predisposição Genética para Doença , Melanoma/genética , Melanoma/patologia , Adulto , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Melanoma/epidemiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Neoplasias Cutâneas , Melanoma Maligno CutâneoRESUMO
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.
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Genes Neoplásicos/genética , Predisposição Genética para Doença/genética , Testes Genéticos/normas , Melanoma/epidemiologia , Melanoma/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Quinase 4 Dependente de Ciclina , Inibidor p16 de Quinase Dependente de Ciclina/genética , Dinamarca/epidemiologia , Mutação em Linhagem Germinativa/genética , Humanos , Fator de Transcrição Associado à Microftalmia , Receptor Tipo 1 de Melanocortina , Proteínas Supressoras de Tumor , Ubiquitina TiolesteraseRESUMO
Known melanoma predisposition genes only account for around 40% of high-density melanoma families. Other rare mutations are likely to play a role in melanoma predisposition. RAD51B plays an important role in DNA repair through homologous recombination, and inactivation of RAD51B has been implicated in tumorigenesis. Thus RAD51B is a good candidate melanoma susceptibility gene, and previously, a germline splicing mutation in RAD51B has been identified in a family with early-onset breast cancer. In order to find genetic variants associated with melanoma predisposition, whole-exome sequencing was carried out on blood samples from a three-case cutaneous melanoma family. We identified a novel germline RAD51B nonsense mutation, and we demonstrate reduced expression of RAD51B in melanoma cells indicating inactivation of RAD51B. This is only the second report of a germline truncating RAD51B mutation. While this case report is consistent with melanoma being part of the RAD51B cancer spectrum further population-based screening of large case-control sample series will be needed to definitively establish if this is the case.
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Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Melanoma/genética , Neoplasias Cutâneas/genética , Proteínas de Ligação a DNA/análise , Humanos , Imuno-Histoquímica , Pessoa de Meia-IdadeRESUMO
Twenty years ago, the first familial melanoma susceptibility gene, CDKN2A, was identified. Two years later, another high-penetrance gene, CDK4, was found to be responsible for melanoma development in some families. Progress in identifying new familial melanoma genes was subsequently slow; however, with the advent of next-generation sequencing, a small number of new high-penetrance genes have recently been uncovered. This approach has identified the lineage-specific oncogene MITF as a susceptibility gene both in melanoma families and in the general population, as well as the discovery of telomere maintenance as a key pathway underlying melanoma predisposition. Given these rapid recent advances, this approach seems likely to continue to pay dividends. Here, we review the currently known familial melanoma genes, providing evidence that most additionally confer risk to other cancers, indicating that they are likely general tumour suppressor genes or oncogenes, which has significant implications for surveillance and screening.